Journal articles on the topic 'Chemokine biology; cancer biology; tumour immunology'
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Aldinucci, Donatella, and Alfonso Colombatti. "The Inflammatory Chemokine CCL5 and Cancer Progression." Mediators of Inflammation 2014 (2014): 1–12. http://dx.doi.org/10.1155/2014/292376.
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Until recently, inflammatory chemokines were viewed mainly as indispensable “gate keepers” of immunity and inflammation. However, updated research indicates that cancer cells subvert the normal chemokine system and these molecules and their receptors become important constituents of the tumor microenvironment with very different ways to exert tumor-promoting roles. The CCR5 and the CCL5 ligand have been detected in some hematological malignancies, lymphomas, and a great number of solid tumors, but extensive studies on the role of the CCL5/CCR axis were performed only in a limited number of cancers. This review summarizes updated information on the role of CCL5 and its receptor CCR5 in cancer cell proliferation, metastasis, and the formation of an immunosuppressive microenvironment and highlights the development of newer therapeutic strategies aimed to inhibit the binding of CCL5 to CCR5, to inhibit CCL5 secretion, or to inhibit the interactions among tumor cells and the microenvironment leading to CCL5 secretion.
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Eyileten, Ceren, Kinga Majchrzak, Zofia Pilch, Katarzyna Tonecka, Joanna Mucha, Bartlomiej Taciak, Katarzyna Ulewicz, et al. "Immune Cells in Cancer Therapy and Drug Delivery." Mediators of Inflammation 2016 (2016): 1–13. http://dx.doi.org/10.1155/2016/5230219.
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Recent studies indicate the critical role of tumour associated macrophages, tumour associated neutrophils, dendritic cells, T lymphocytes, and natural killer cells in tumourigenesis. These cells can have a significant impact on the tumour microenvironment via their production of cytokines and chemokines. Additionally, products secreted from all these cells have defined specific roles in regulating tumour cell proliferation, angiogenesis, and metastasis. They act in a protumour capacityin vivoas evidenced by the recent studies indicating that macrophages, T cells, and neutrophils may be manipulated to exhibit cytotoxic activity against tumours. Therefore therapy targeting these cells may be promising, or they may constitute drug or anticancer particles delivery systems to the tumours. Herein, we discussed all these possibilities that may be used in cancer treatment.
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Theodoraki, Marie-Nicole, Saumendra N. Sarkar, Francesmary Mogundo, Robert P. Edwards, and Pawel Kalinski. "Separate molecular pathways mediate anti-tumor versus tumor-promoting aspects of Poly-I:C signaling in cancer microenvironments." Journal of Immunology 198, no. 1_Supplement (May 1, 2017): 196.7. http://dx.doi.org/10.4049/jimmunol.198.supp.196.7.
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Abstract Background We have previously shown that Poly-I:C, a frequently used adjuvant, induces both the CTL-attracting chemokines and Treg attractants. Here we evaluated the molecular pathways, which lead to the induction of chemokines by poly-I:C in TME and different types of tumor-associated cells, in order to develop improved adjuvants which selectively attract the desirable effector cells rather than suppressive cells. Methods Isolated cells or human cancer biopsies were cultured for 0.5–48 hours in the absence or presence of one of two synthetic TLR3 ligands Poly-I:C (non-selective activator of TLR3 and helicases) rintatolimod (selective TLR3 ligand), in the absence or presence of a COX-1/2 inhibitor, NF-kB- and TNFa inhibitors. mRNA assays, confocal microscopy, ELISA, chemotaxis assays and molecular biology assays were used to analyze the chemokine production and tumor-associated suppressive factors. Results We observed that poly-I:C induced activation of NF-kB- and COX-2 pathways leading to induction of COX2-dependent suppressive factors and Treg- and MDSC-attracting chemokines. These undesirable effects were blocked with inhibitors of both NF-kB- or COX-2 pathways. In contrast rintatolimod selectively induced the desirable chemokines, which were associated with lack of direct activation of NF-kB- or COX-2 pathways, and strongly suppressed attraction of Tregs and MDSCs, with elevated CTL attraction in ex vivo migration assays. Conclusion Our data implicates an important new role of helicases by the induction of tumor-promoting factors by dsRNA and points out to new targets to enhance the immunogenic and antitumor activities of adjuvants.
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Leick, Marion, Julie Catusse, and Meike Burger. "The Atypical Chemokine Receptor CRAM Mediates CCL19 Transcytosis through Endothelial Cells and Modulates CCL19 Activation of Non-Hodgkin Lymphoma B Cells." Blood 114, no. 22 (November 20, 2009): 2672. http://dx.doi.org/10.1182/blood.v114.22.2672.2672.
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Abstract Abstract 2672 Poster Board II-648 Introduction: Chemokines work as cellular recruitment molecules. Specific combinations of chemokines, receptors, and adhesion molecules determine which subgroups of leukocytes migrate and what their destinations are. Chemokine receptor expression and activation on malignant cells may be involved in the growth, survival and migration of cancer cells as well as in the tumor vascularisation. CCR7, by binding the chemokines CCL19 and CCL21, is centrally involved in B cell localisation to the secondary lymphoid organs and therefore implicated in lymphadenopathy of various non-hodgkin lymphomas (NHL). In addition to chemokine receptors that have been cloned and described, various orphan receptors with a chemokine receptor-like structure are still not characterized. Atypical, non-signaling chemokine receptors are members of a newly described class of receptors and have been implicated with chemokine clearance and influencing of other signalling receptors. They are consequently considered as potent immuno-modulators and as anti-inflammatory factors and are implicated in progression of cancer. Among these receptors, we are investigating the role of the orphan chemokine (C-C motif) receptor-like 2 (CCRL2), also known as CRAM, a receptor expressed on endothelial cells and B cells in a maturation stage dependent manner, but for which functions and ligands are poorly characterized so far. In an effort to elucidate the role of CRAM and its implication in neoplasias, we have focussed research on identification of ligands and the implication of CRAM in regulating B cell migration in samples from healthy donors and from non-Hodgkin lymphomas. Methods: We characterised the receptor's expression profile by flow cytometry in peripheral blood, bone marrow and lymph node sections of different B cell NHL and correlated it to expression levels of CCR7 and CXCR4. In addition, a screening for ligands was performed using radiolabelled binding assays. The role of CRAM was elucidated using various functional assays, internalisation and transcytosis experiments. Results: We show that CRAM is an alternative, but non-signaling receptor for the CCR7-activating chemokine CCL19. CRAM is constitutively recycling to and from the cell surface and internalizing the chemokine without degrading it. We found that the receptor is responsible for transcytosis of CCL19 through endothelial cell layers and subsequent presentation, a crucial step in homing of leukocytes to the lymph nodes. On the other hand, when expressed on B cells, CRAM interferes in CCL19 binding to CCR7. We thereby show that CRAM can act as an integrator of different signals, by binding different chemokines and controlling their activity toward surrounding ligands. Chemotaxis experiments demonstrate that CRAM is a negative modulator of CCL19 B cell recruitment. In addition, we have found increased expression in activated B cells, dendritic cells, and also in the B cell malignancies chronic lymphocytic leukemia (B-CLL) and pre-B cell acute lymphoblastic leukemia (pre-B ALL), and are currently evaluating CRAM as a possible prognostic marker in various B-NHLs. Conclusions: CRAM is a newly identified member of the silent or atypical chemokine receptor group, already known for modulating chemokine availability, together with D6, DARC and CCX-CKR. We have shown here that it contributes to lymphocyte recruitment into peripheral lymphoid tissue by presenting CCL19 on endothelium. It is also involved in CCR7 driven recruitment of B cells by regulating CCL19 availability. Expression of CRAM differs in B cell malignancies for which both CCR7 ligands, CCL19 and CCL21, have already been shown to be implicated in the development of lymphadenopathies. We therefore suggest that CRAM is an additional player and potential biomarker in determining outcome and development of disease. Disclosures: No relevant conflicts of interest to declare.
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Yuan, Ming, Ha Zhu, Junfang Xu, Yuanyuan Zheng, Xuetao Cao, and Qiuyan Liu. "Tumor-Derived CXCL1 Promotes Lung Cancer Growth via Recruitment of Tumor-Associated Neutrophils." Journal of Immunology Research 2016 (June 29, 2016): 1–11. http://dx.doi.org/10.1155/2016/6530410.
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Neutrophils have a traditional role in inflammatory process and act as the first line of defense against infections. Although their contribution to tumorigenesis and progression is still controversial, accumulating evidence recently has demonstrated that tumor-associated neutrophils (TANs) play a key role in multiple aspects of cancer biology. Here, we detected that chemokine CXCL1 was dramatically elevated in serum from 3LL tumor-bearing mice. In vitro, 3LL cells constitutively expressed and secreted higher level of CXCL1. Furthermore, knocking down CXCL1 expression in 3LL cells significantly hindered tumor growth by inhibiting recruitment of neutrophils from peripheral blood into tumor tissues. Additionally, tumor-infiltrated neutrophils expressed higher levels of MPO and Fas/FasL, which may be involved in TAN-mediated inhibition of CD4+ and CD8+ T cells. These results demonstrate that tumor-derived CXCL1 contributes to TANs infiltration in lung cancer which promotes tumor growth.
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Braza, Mounia, Therese Rousset, Majda Saifi, Guillaume Cartron, Sylvie Lafaye de Micheaux, Helene Sicard, Patrick Squiban, Valérie Costes, and Jean-Francois Rossi. "In Follicular Lymphoma (FL), γδt-Lymphocytes (γδT) Are Present and Expandable from Peripheral Blood and Rare in Tumour Lymph Nodes, Mostly in Peri-Follicular Areas." Blood 112, no. 11 (November 16, 2008): 1773. http://dx.doi.org/10.1182/blood.v112.11.1773.1773.
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Abstract Background: The tumour microenvironment plays an important role in the biology of FL. Different cell populations have been explored, including T-regulatory lymphocytes, macrophages, and T-cell subpopulation. The involvement of γδT in lymph nodes from FL patients or from inflammatory diseases has been rarely documented. So far, their histological pattern and prognosis significance are unknown and must be defined in order to develop new therapeutic programs including in vivo or ex vivo expansion of γδT, as developed particularly in B-cell malignancies by us and different groups. In this study, we analyzed from FL patients 1/the number of circulating γδT and their ex vivo expansion, 2/ the presence and distribution of γδT in tumour lymph nodes, and different chemokines, in comparison to inflammatory lymph nodes (ILN), by immunochemistry. Patients and Methods: Circulating γδT cells were counted in peripheral blood from patients having FL by FACS analysis. Blood samples from 34 patients were collected and expanded in vitro by using γδT ligands, referred to as “phosphoantigens”, including IPH1101 (used in clinical trials) and interleukin 2. Tumour samples from 51 patients (35 at diagnosis and 16 at relapse) having FL were collected from a single institution. Immunochemistry was used to study numbers and distribution of CD8, γδT cells, and the expression of CCL19, 21 and SDF1 chemokines. CCR7/γδT cells were analyzed by double immunofluorescence. Results were compared to 28 samples from patients having ILN. Results: The mean of circulating γδT was 0.36% (0.03–2.5) representing a mean of 2.2% of the CD3 cells. The mean percentage of γδT cells obtained after in vitro culture was 85% (2.1–95) with a mean 220-fold expansion (2-1050). The median number of γδT cells (cells/mm2) in FL lymph node was 18 versus 47.5 in the ILN (mean: 30 versus 82,5), P<.00001. The median of CD8 cells was 1235 in FL as compared to 1503 in ILN (mean: 1290 versus 1524). CD8+ cells had different localization (i.e. intra-and /or extra-follicular localization), but γδT were strictly peri-follicular in both clinical situations. Immunohistochemistry of the high endothelial venules (HEVs) and lymphatic vessels (LV) of 14 FL and 14 ILN were performed. We observed a significant difference (P= 2.10−7) in the expression of only the CCL19 chemokine between FL and ILN, with a poor staining for CCL19 in FL lymph nodes. CCL21 and CXCL12 do not present a difference in their expression levels. The stroma was reactive for all these chemokines, while the SDF1/CXCL12 chemokine shows a topographic difference in the distribution of stromal cells around HEV. Conclusions: These observations suggest that γδT cells are present and expandable in PB from patients having FL including patients with advanced disease. In addition, γδT are not abundant in lymph nodes of patients with FL compared to ILN, but γδT conserve their CCR7+ phenotype. This deficiency could be explained by migratory problems provoked by a lack of CCL19 chemokine expression. As γδT have been demonstrated to kill tumour cells, including B-malignant cells, they could be considered as essential targets for immune therapy in different cancers including B-cell malignancies, but their activation and trafficking has to be considered.
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Mazur, Grzegorz, Ilona Kryczek, Tomasz Wrobel, Dorota Dlubek, Aleksandra Klimczak, Emilia Jaskula, Michal Jelen, Andrzej Lange, and Kazimierz Kuliczkowski. "CCL2 Chemokine Gene Expression in Lymph Nodes May Have Prognostic Value in Non-Hodgkin’s Lymphoma." Blood 108, no. 11 (November 16, 2006): 4644. http://dx.doi.org/10.1182/blood.v108.11.4644.4644.
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Abstract Background: Non-Hodgkin’s lymphomas (nHL) constitute complex group of lymphoproliferative disorders in which clinical outcome is difficult to predict at the moment of diagnosis. Formation of International Prognostic Index has provided criteria dividing patients into groups of risk, but still new prognostic factors are being searched. There are several reports that some chemokines including CCL2 play a role in progression of solid tumours (bladder, ovarian, non-small cell lung cancer) and increased level of CCL2 has been found in myeloma multiple. CCL2 is the chemokine produced by tumour cells and some stromal cells, such as: fibroblasts, endothelial cells and monocytes. CCL2 is chemoattractant for monocytes, T, NK and dendritic cells and basophlis. CCL2 has also angiogenic activity and is necessary for tumour growth and metastatic process. Aim: The purpose of this study was to evaluate gene expression of CCL2 chemokine in lymphoma and reactive lymph nodes. Material and methods: CCL2 gene expression was determined in 37 lymph nodes of lymphoma patients (26 B-cell lymphoma: 12 females and 14 males aged 26–73 years; 4 T-cell lymphoma: males aged 41–81 years; 7 Hodgkin’s lymphoma: 4 females and 3 males aged 21–58 years) and 25 reactive lymph nodes (15 females, 10 males, aged 18–59 years, median age 32 years). Gene expression was determined by the reverse transcription (RT)-polymerase chain reaction method. Scale of expression was 0–3 AU. Statistical analysis was performed using Kruskall-Wallis and Mann-Witney tests (p<0,05). Results: In lymphoma lymph nodes CCL2 expression was significantly higher (2–3 AU) than in reactive lymph nodes (p=0,0008). Increased CCL2 expression was detected in 19/26 (73%) B-cell lymphoma lymph nodes and all (4/4, 100%) T-cell lymphomas. In reactive lymph nodes 2 AU expression was observed in 7/25 cases (28%). Particularly high expression characterized diffuse large B-cell lymphomas and Burkitt lymphomas. Patients with high CCL2 expression had significantly shorter survival than those with low expression (p=0,004). There was positive correlation between CCL2 expression and Ki-67 proliferation marker (p<0,05; coefficient 0,39). Conclusions: CCL2 expression is higher in B-cell lymphoma lymph nodes than in reactive lymph nodes. Multivariate analysis has proved CCL2 as independent prognostic factor in nHL.
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Miyazaki, Yukihiro, Hiroshi Fujiwara, Toshiki Ochi, An Jun, Toshiaki Shirakata, Kozo Nagai, Sachiko Okamoto, et al. "Dual Engineering of Human CD8+ T-Cells with WT1-Specific TCR Gene and Chemokine Receptor Gene Transfer Confers Functionally Strengthened Anti-Cancer Reactivity." Blood 116, no. 21 (November 19, 2010): 4295. http://dx.doi.org/10.1182/blood.v116.21.4295.4295.
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Abstract Abstract 4295 Background & Purpose: Currently a novel adoptive therapy with engineered T-cells using cancer antigen-specific T-cell receptor (TCR) gene transfer has attracted the attention as a challenging option for cancer treatment. However, reported efficacy from clinical trials using TCR-gene transfer was generally less than expected. In concurrent with the major issue of generation of mispaired TCRs between introduced and endogenous TCR α/β chains, the less accumulation of adoptively infused engineered T-cells at local tumor site in number could also impede the clinical efficacy. Therefore, for the purpose of sufficient accumulation of adoptively transferred tumor-specific T cells into local tumor sites, we set out to examine the feasibility of dual transduction of cancer antigen-specific TCR gene and chemokine receptor gene into human T-cells. Methods: HLA-A*2402-restricted and WT1235-243-specific TCR α/β genes were cloned into a novel GaLV-pseudotyped retroviral vector carrying silencers for endogenous TCR-a/b chains. With retronectin (TakaraBio, Inc.)-coated plate, WT1-specific TCR-α/β genes were introduced into normal CD8+ T-cells with upto more than 50% of WT1-tetramer positivity. On the other hand, using QRT-PCR, we comprehensively screened the chemokine expression profiles of pre-determined HLA-A*2402+ human leukemia cell lines (n=13) and lung cancer cell lines (n=4) which were all WT1-expressing and sensitive to WT1235-243-specific TCR-transduced CD8+ T-cells. Then, the receptor gene for selected chemokine was cloned and inserted into retroviral vector. Expression and function of induced chemokine receptor into Jurkat cells was examined by flowcytometer and transwell experiment. Next, the chemokine receptor gene was introduced into WT1-specific TCR introduced CD8+ T-cells. Migration ability toward target chemokine, and cytotoxicity against the target tumor cells of double-gene transfectans were examined by transwell experiment and 51Cr-releasing assay, respectively. Finally, the combined anti-cancer effect of double-gene transfectants was examined in a novel assay consisted of transwell part and cytotoxicity assay determined by concentration of LDH released from target tumor cells in the bottom well, which were killed by migrated double-gene transfectants from the upper well towards the chemokine produced by target tumor cells. Results: CCL2 chemokine was abundantly produced by some of human lung cancer cell lines and leukemia cell lines. Additionally, receptor for CCL2 (CCR2) was not expressed in activated CD8+ T-cells. Thus, we selected CCL2/CCR2 interaction for this system. CCR2 gene was successfully transduced into Jurkat cells and conferred migration activity towards CCL2 and CCL2 producing lung cnacer cell line LK79 and leukemia cell line KH88. CCR2 gene was also successfully introduced into WT1-specific TCR gene trnasduced CD8+ T-cells. The double-gene transfectants successfully migrated towards CCL2-producing LK79 and KH88 cells. Eventually, in our novel assay system, only double genes-transduced CD8+ T cells in the upper-well, but not single WT1-specific TCR gene-transduced CD8+ T-cells, could migrate towards LK79 cells in the bottom-well and efficiently killed LK79 cells. Background: Although further investigations are warranted, the dual T-cell engineering of human T-cells with chemokine receptor gene and our novel avidity-enhanced tumor-specific TCR gene may be able to more efficiently accumulate engineered T-cells at local tumor sites, which may enhance the immediate anti-tumor effect of adoptively transferred such engineered T-cells. Disclosures: No relevant conflicts of interest to declare.
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Fang, Yeying, Fraser C. Henderson, Qiong Yi, Qianqian Lei, Yan Li, and Nianyong Chen. "Chemokine CXCL16 Expression Suppresses Migration and Invasiveness and Induces Apoptosis in Breast Cancer Cells." Mediators of Inflammation 2014 (2014): 1–9. http://dx.doi.org/10.1155/2014/478641.
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Background.Increasing evidence argues that soluble CXCL16 promotes proliferation, migration, and invasion of cancer cellsin vitro. However, the role of transmembrane or cellular CXCL16 in cancer remains relatively unknown. In this study, we determine the function of cellular CXCL16 as tumor suppressor in breast cancer cells.Methods.Expression of cellular CXCL16 in breast cancer cell lines was determined at both RNA and protein levels.In vitroandin vivostudies that overexpressed or downregulated CXCL16 were conducted in breast cancer cells.Results.We report differential expression of cellular CXCL16 in breast cancer cell lines that was negatively correlated with cell invasiveness and migration. Overexpression of CXCL16 in MDA-MB-231 cells led to a decrease in cell invasion and migration and induced apoptosis of the cells; downregulation of CXCL16 in MCF-7 cells increased cell migration and invasiveness. Consistent with thein vitrodata, CXCL16 overexpression inhibited tumorigenesisin vivo.Conclusions.Cellular CXCL16 suppresses invasion and metastasis of breast cancer cellsin vitroand inhibits tumorigenesisin vivo. Targeting of cellular CXCL16 expression is a potential therapeutic strategy for breast cancer.
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Lachota, Mieszko, Daniel Alfredo Palacios, Dennis Clement, Eivind Heggernes Ask, Hanna Julie Hoel, Merete Thune Wiiger, Marianna Vincenti, Magdalena Winiarska, Radoslaw Zagozdzon, and Karl-Johan Malmberg. "Innate-like Chemokine Receptor Profile and Migratory Behaviour By Terminally Differentiated and Educated NK Cells." Blood 136, Supplement 1 (November 5, 2020): 24–25. http://dx.doi.org/10.1182/blood-2020-140944.
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Natural Killer (NK) cells play an essential role in cancer surveillance and have a unique capability of spontaneous cytotoxicity against cancer cells. The human NK cell repertoire is functionally diversified through a tightly regulated differentiation process characterized by an early transition from CD56bright to CD56dim NK cells, followed by coordinated changes in expression of inhibitory receptors, including NKG2A and killer cell immunoglobulin-like receptors (KIR). The acquisition of self HLA class I binding KIRs during NK cell differentiation tunes the cytotoxic potential of NK cells in a process termed education, characterized by increased loading of granzyme B in dense core granules. Although NK cell differentiation and education are critical determinants of the functional potential of the cell, little is known about how these events shape the migratory behavior of NK cells. To mediate appropriate and directed immune response against cancer, NK cells must be capable of migration to the tumor site. This process is mediated by chemokines, which guide cell migration by binding to their specific receptors. For example, in multiple myeloma, CXCR3 and CCR5 ligands (MIG, IP-10, and MIP-1a) are significantly upregulated in the bone marrow compared to healthy controls, affecting the composition of immune cells in the tumor microenvironment. In order to delineate the homing patterns of distinct NK cell subsets, we used high-dimensional flow cytometry combined with functional assays to map the NK cell chemokine receptor expression and migratory behavior. We screened resting and cytokine/feeder cell stimulated peripheral blood NK cells for the expression of a panel of 20 chemokine receptors (A). Based on CD56, CD57, NKG2A, and KIR expression, NK cells were divided into 6 phenotypically and functionally distinct subsets that were ordered according to their differentiation status (B). We found that the expression of CX3CR1, CXCR1, CXCR2, and CMKLR1 gradually increased during differentiation, whereas the expression of CXCR3, CCR7, and CCR5 was lower in more differentiated NK cells. CXCR4, CCR4, and CCR2 expression was relatively uniform across all subsets. Interestingly, CCR1 and CXCR6 were expressed mainly on less differentiated NKG2A+ CD56dim NK cells (B). Next, we stratified the chemokine receptor expression on mature KIR+ NK cells based on the expression of self (educated) or non-self KIR (uneducated). Educated NK cells expressed CXCR1, CX3CR1, CCR5, and CMKLR1 at higher levels than the uneducated NK cells. Conversely, CXCR3 was expressed at lower levels on educated NK cells (C). No difference was observed for CXCR2 expression. To determine whether the observed differences in chemokine receptor expression translate into altered chemokine responsiveness between the subsets, we combined the transwell system with multicolor flow cytometry. We found that the chemokine-induced migration capability of NK cells correlated closely with the expression level of corresponding chemokine receptor, leading to subset specific responses to various chemokine gradients (D). The present results show that peripheral blood NK cell chemokine receptor profile changes in a coordinated fashion during NK cell differentiation and is further influenced by the expression of self-specific KIR. Interestingly, receptors which expression declines during NK cell differentiation (CCR5, CCR7, and CXCR3) are commonly associated with adaptive T cell responses to viruses, whereas receptors that are upregulated along the differentiation axis (CXCR1, CXCR2, CX3CR1, CMKLR1) are typical for neutrophils and macrophages as a part of the innate immune response. Thus, our results suggest that NK cell differentiation and education processes together shape the NK cell migratory capabilities to promote homing of the most functional NK cell subsets to the site of inflammation and serve as the first line of defense in the immune response to pathogens and tumors. Figure Disclosures Malmberg: Fate Therapeutics: Consultancy, Patents & Royalties; Vycellix: Membership on an entity's Board of Directors or advisory committees.
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Hong, Cheol Yi, Pawel Kalinski, Hyeoung-Joon Kim, and Je-Jung Lee. "The Lymphoid Chemokine CCL21 Enhances the Migration- and CTL-Inducing Functions of Dendritic Cells." Blood 118, no. 21 (November 18, 2011): 1127. http://dx.doi.org/10.1182/blood.v118.21.1127.1127.
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Abstract Abstract 1127 The migration of dendritic cells (DCs) to secondary lymphoid organs is very important to elicit an adaptive immune response in cancer immunotherapy. Here, we show the effect of lymphoid cytokine on the ability of maturing DCs to migrate in response to the lymph node-associated chemokines. The secondary-lymphoid organ chemokine (SLC/CCL21) during DC maturation dramatically enhanced DC migratory capacity responding to CCL21 and CCL19, and, moreover, produced strongly enhanced cytotoxic T cells, although it did not affect the expression of cell surface markers such as CD80, CD83, CD86, and CCR7 and the production of cytokines such as IL-12p70, IL-10, and IL-23. Mature DCs (mDCs) exposed by chemokine produced higher levels of CXCL10 (IP-10) that is one of the chemokines involved in Th1 attraction, but did not affect the production of Th2-attracting cytokine CCL22, compared with unstimulated mDCs. CCL21-exposed DCs induced strongly enhanced numbers of the interferon-g (IFN-g)-expressing antigen-specific CD8+ T cells against tumor-specific antigens in an CXCL10-dependent manner. Cytotoxic CD8+ T cells stimulated with CCL21-exposed DCs expressed higher level of IFN-g than those stimulated with control mDCs. Interestingly, generation of cytotoxic T cells (CTLs) stimulated by TNFa/IL-1b/IL-6/PGE2-treated DCs (sDCs) supplemented with IP-10 produced strong cytotoxic T cells expressing higher level of IFN-g. Tetramer assay showed that CCL21-treated DCs enhanced generation of antigen-specific CTLs. Taken together, our data suggest that mDCs pre-stimulated by chemokine CCL21 enhanced migratory capacity to secondary lymphoid organs and produced strong cytotoxic T cells via IP-10 signaling pathway. Disclosures: No relevant conflicts of interest to declare.
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Toledo, Belén, Manuel Picon-Ruiz, Juan Antonio Marchal, and Macarena Perán. "Dual Role of Fibroblasts Educated by Tumour in Cancer Behavior and Therapeutic Perspectives." International Journal of Molecular Sciences 23, no. 24 (December 8, 2022): 15576. http://dx.doi.org/10.3390/ijms232415576.
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Tumours are complex systems with dynamic interactions between tumour cells, non-tumour cells, and extracellular components that comprise the tumour microenvironment (TME). The majority of TME’s cells are cancer-associated fibroblasts (CAFs), which are crucial in extracellular matrix (ECM) construction, tumour metabolism, immunology, adaptive chemoresistance, and tumour cell motility. CAF subtypes have been identified based on the expression of protein markers. CAFs may act as promoters or suppressors in tumour cells depending on a variety of factors, including cancer stage. Indeed, CAFs have been shown to promote tumour growth, survival and spread, and secretome changes, but they can also slow tumourigenesis at an early stage through mechanisms that are still poorly understood. Stromal–cancer interactions are governed by a variety of soluble factors that determine the outcome of the tumourigenic process. Cancer cells release factors that enhance the ability of fibroblasts to secrete multiple tumour-promoting chemokines, acting on malignant cells to promote proliferation, migration, and invasion. This crosstalk between CAFs and tumour cells has given new prominence to the stromal cells, from being considered as mere physical support to becoming key players in the tumour process. Here, we focus on the concept of cancer as a non-healing wound and the relevance of chronic inflammation to tumour initiation. In addition, we review CAFs heterogeneous origins and markers together with the potential therapeutic implications of CAFs “re-education” and/or targeting tumour progression inhibition.
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Hayes, A. J., P. Burgoyne, R. Cooper, M. Pingen, G. J. Graham, and J. Campbell. "Using chemokine sorting to imrpove NK cell function in an anti-tumour model." Cytotherapy 21, no. 5 (May 2019): S28. http://dx.doi.org/10.1016/j.jcyt.2019.03.341.
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Colmone, Angela, Veena Krishnamoorthy, and Dorothy A. Sipkins. "Dynamic In Vivo Imaging Reveals That Leukemia-Induced Changes in the Bone Marrow Microenvironment Alter Mechanisms of Metastasis." Blood 110, no. 11 (November 16, 2007): 2805. http://dx.doi.org/10.1182/blood.v110.11.2805.2805.
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Abstract Tissue microenvironments have been shown to critically regulate cancer cell survival and proliferation. Conversely, while tumor growth can induce neovascularization, the impact of other tumor-induced changes in the microenvironment are less well understood. Here we utilize a xenograft model of Nalm-6 pre-B acute lymphoblastic leukemia (ALL) in SCID mice to examine how tumor growth alters the bone marrow (BM) microenvironment. Using dynamic confocal and multiphoton in vivo imaging, we find that tumor growth dramatically down-regulates expression of the chemokine SDF-1 in the BM microvasculature in areas of leukemic proliferation. SDF-1 has been shown to play a key role in cancer cell metastasis for numerous cell types including Nalm-6, and directs initial Nalm-6 homing to specific SDF-1-positive vascular beds. In contrast, we found that Nalm-6 introduced in mice previously engrafted with leukemia home to SDF-1-negative vasculature, predominantly at the advancing tumor margin. Furthermore, inhibition of chemokine signaling by pertussis toxin pre-treatment of Nalm-6 cells demonstrates that Nalm-6 homing in engrafted mice is chemokine-independent. In summary, these findings suggest that leukemic growth profoundly alters the mechanisms underlying the metastatic process by inducing changes in the host vascular microenvironment. These changes may increase the efficiency of the metastatic process and/or the advancement of the tumor margin. Therapies directed at blocking tumor metastases, therefore, may need to be tailored according to tumor stage.
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Mazur, Grzegorz, Emilia Jaskula, Ilona Kryczek, Dorota Dlubek, Tomasz Wrobel, Aleksandra Butrym, Andrzej Lange, and Kazimierz Kuliczkowski. "Gene Expression for Chemokine Receptors Influences Survival of Non-Hodgkin Lymphoma Patients." Blood 116, no. 21 (November 19, 2010): 3103. http://dx.doi.org/10.1182/blood.v116.21.3103.3103.
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Abstract Abstract 3103 Non-Hodgkin's lymphoma (nHL) represent heterogenous group of lymphoid malignancies derived from B and T lymphocytes, NK cells or histiocytes. Most of lymphomas are B-cell origin. Lymphoma cells can migrate to other organs and their migration could be linked to chemokines and their receptors. Chemokine receptors are expressed by many cell populations, including lymphoid cells, and their main function is lymphocytes. Chemokine receptors guide lymphocytes homing, chemotaxis, adhesion and interplaying between immunologic system response cells. They are also responsible for cancer metastasis, including also dissemination of Hodgkin's and non-Hodgin's lymphomas. The purpose of the study was to determinate expression of genes coding chemokine receptors: CXCR4, CCR1, CCR2a, CCR2b, CCR3, CCR5, CCR7 and CCR8 in lymphoma lymph nodes comparing to their expression in reactive lymph nodes. We also wanted to analyze the influence of chemokine receptor gene expression on lymphoma patient survival. Methods: Chemokine receptor gene expression was evaluated in 63 lymphoma lymph nodes taken from patients (31 women and 32 men, aged 18–81 years; median age 43 years) at the moment of diagnosis. In 25 samples of reactive lymph nodes (taken from 15 women and 10 men; aged 18–59; median age 32 years) expression of chemokine genes was also studied as a control group. Gene expression of chemokine receptors CXCR4, CCR1, CCR2a, CCR2b, CCR3, CCR5, CCR7 and CCR8 was measured by reverse transcription (RT)-polymerase chain reaction method. Gene expression was estimated in arbitrary units (AU) from 0 to 3 AU points scale. PCR was conducted using primer pairs for CXCR4 (sens GAC CGC TAC CTG GCC ATC, antisens GGC AGC CAA CAG GCG AAGg A, 345 bp), CCR2a (sens GTA TCT CTC GGT GTT CTT CC, antisens TCT AGG CTC CTT CTT TGT CCT G, 271 bp), CCR2b (sens GTA TCT CTC GGT GTT CTT CC, antisens ACC AGC CGA GAC TTC CTG CT, 163 bp) CCR3 (sens TCC TTC TCT CTT CCT ATC AAT, antisens GGC AAT TTT CTG CAT CTA, 312 bp), CCR5 (sens AAT CTT CTT CAT CAT CCT CC, antisens TCT CTG TCA CCT GCA TAG C, 506 bp), CCR7 (sens CTG GTG GTG GCT CTC CTT GT, antisens GCC AGG TTG AGC AGG TAG GT, 271 bp), CCR8 (sens GGT TGG TGC TCA TTG TGG TC, antisens AGT CTA CGC TGG AGG AAC GG, 345 bp). Statistical analysis was performed using the CSS Statistica for Windows (version 7.0) software. Probability values <0.05 were considered statistically significant. Results: There was significantly higher expression of CCR1 and CCR8 gene in lymphoma lymph nodes comparing to controls (p<0.05), while CCR5 and CCR7 gene expression was significantly lower in lymphoma lymph nodes (p<0.05) comparing to reactive lymph nodes. CXCR4, CCR2a, CCR2b, CCR3 expression did not differ between lymphoma and control groups. The patients with higher expression of CCR7 gene had significantly longer survival comparing to those with lower expression (p=0.048). Expression of CCR7 was negatively correlated with IPI (p=0.036, coefficient = -0.32). Higher expression of CCR5 gene was positively correlated with Ki-67 (p=0,016, coefficient = 0.34), stage of disease (p=0.048, coefficient = 0.029) and international prognostic index score - IPI (p=0,047, coefficient = 0.298). We also found positive correlation between CCR8 gene expression and IPI (p=0.039, coefficient = 0.32). Conclusions: Lower expression of CCR7 gene is combined with longer survival of nHL patients. As there are positive correlations between CCR5 expression and Ki-67 proliferation marker and IPI as well as CCR8 and IPI in non-Hodgkin's lymphoma, those receptors can promote tumour progression. Disclosures: No relevant conflicts of interest to declare.
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Philipp-Abbrederis, Kathrin, Ken Herrmann, Margret Schottelius, Matthias Eiber, Carlos Gerngroß, Elke Pietschmann, Katharina Lückerath, et al. "[68Ga]Pentixafor: A Novel PET Tracer for Imaging CXCR4 Status in Patients with Multiple Myeloma." Blood 124, no. 21 (December 6, 2014): 2014. http://dx.doi.org/10.1182/blood.v124.21.2014.2014.
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Abstract Chemokine receptors form a large family of G-protein coupled receptors that mediate chemotaxis of cells towards a gradient of chemokines. The C-X-C chemokine receptor-4 (CXCR4, also known as fusin, CD184) exerts its biological effects by binding its ligand CXCL12 (or Stromal-cell derived factor-1, SDF-1) which activates downstream pathways, ultimately resulting in altered cell adhesion and cell homing. Physiologically, the CXCR4/CXCL12 interaction plays a pivotal role in the recruitment and homing of hematopoietic stem/ progenitor cells (HSPC) and immune cells. In cancer, CXCR4 expression is associated with tumor dissemination and prognosis. Using multiple myeloma (MM) as an exemplary CXCR4-expressing cancer entity, we report the evaluation of [68Ga]Pentixafor-PET as a method for in vivo mapping of CXCR4 expression density by means of Positron Emission Tomography. [68Ga]Pentixafor-PET provides images with excellent specificity and contrast when assessed in mice xenografted with human CXCR4-positive MM. We next analyzed CXCR4 expression using [68Ga]Pentixafor-PET in a cohort of fourteen patients with advanced MM. These patients also underwent standard [18F]Fluoro-Deoxyglucose-PET (FDG-PET). Nine of fourteen FDG-PET scans were rated visually positive, whereas ten of fourteen Pentixafor-PET scans revealed MM manifestations. Assessment of blood counts and standard CD34+ flow cytometry did not reveal significant blood count changes or alterations in HSPC frequency associated with tracer application. These data document the first methodology for clinical PET imaging of CXCR4 in a cohort of MM patients. [68Ga]Pentixafor-PET opens a broad field of clinical investigations on CXCR4 expression and regulation in the cancer field and beyond. Disclosures Wester: SCINTOMICS, > Radiopharmaceutical Technology: Employment.
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Siders, William, Yanping Hu, Matthew Gale, Gary Jacques, Robert Fogle, Jacqueline Shields, Carrie Garron, and Johanne Kaplan. "Treatment with the CXCR4 Antagonist AMD3100 Enhances Antibody Mediated Killing in Disseminated Lymphoma Models." Blood 114, no. 22 (November 20, 2009): 2717. http://dx.doi.org/10.1182/blood.v114.22.2717.2717.
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Abstract Abstract 2717 Poster Board II-693 Interactions between chemokines and their receptors play an important role in cancer biology and have been shown to influence several processes such as tumor growth and the development of metastatic lesions. Stromal cell derived factor-1 (SDF-1) is a chemokine that binds to the CXCR4 chemokine receptor and stimulates B cell growth. CXCR4 is frequently over-expressed on tumor cells and the SDF-1/CXCR4 axis has been reported to play a role in promoting survival, angiogenesis and metastasis. The role of the stroma, in particular SDF-1/CXCR4 interactions, in providing a “survival niche” for tumor cells is well described for both hematological and solid tumors. We hypothesized that disruption of the protective microenvironment of tumor cells through antagonism of the SDF-1/CXCR4 axis may enhance the sensitivity of the tumor cells to treatment with anti-cancer agents such as monoclonal antibodies. Mozobil (AMD3100) or its structurally related analog, AMD3465, were used in combination with either Campath (anti-CD52) or Rituxan (anti-CD20) in lymphoma xenograft models to determine whether enhanced tumor protection could be observed. Flow cytometry analysis of lymphoma cell lines confirmed the cell surface expression of high levels of CXCR4 as well as the CD20 and CD52 target antigens. Lymphoma cells were seeded by intravenous injection and tumor-bearing mice were treated with multiple injections of the CXCR4 antagonists AMD3465 or AMD3100 alone or in combination with monoclonal antibodies. Treatment with AMD3465 as a single agent was sufficient to increase survival of the animals compared to untreated controls. In addition, the combination of AMD3465 and Campath showed a synergistic effect with a prolongation of survival greater than that obtained with either agent alone (p<0.01). Similarly, combination of AMD3100 and Rituxan also resulted in a significantly prolonged survival compared to either agent alone (p=0.0340). In vivo imaging using a Raji-luciferase cell line also confirmed the impact of treatment on tumor burden. These results suggest that there is a potential role for CXCR4 antagonists in combination with a B-cell targeted therapy in the treatment of B-cell malignancies in the clinic. Disclosures: Siders: Genzyme Corporation: Employment. Hu:Genzyme: Employment. Gale:Genzyme: Employment. Jacques:Genzyme: Employment. Fogle:Genzyme: Employment. Shields:Genzyme: Employment. Garron:Genzyme: Employment. Kaplan:Genzyme: Employment.
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Carpenter, Ben, Sara Ghorashian, Emma Nicholson, James Edward Griffin, Maryam Ahmadi, Angelika Holler, Barry Flutter, et al. "Targeting Therapeutic T Cells to Tumour Niches." Blood 120, no. 21 (November 16, 2012): 3009. http://dx.doi.org/10.1182/blood.v120.21.3009.3009.
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Abstract Abstract 3009 Background: Interactions between tumour cells and host cells within the microenvironment are important in promoting the development of cancer. Tumor niches provide crucial anti-apoptotic and anti-proliferative signals that drive tumor chemoresistance. The CXCR4-CXCL12 chemokine axis forms a critical component of this niche. CXCL12 produced by stromal cells has direct pro-survival effects upon tumor cells, promotes metastasis and recruits CXCR4-expressing regulatory T cell populations that block anti-tumour immunity. In this study, we have tested the hypothesis that targeting therapeutic T cells to CXCR4-dependent niches will improve eradication of tumours in mice. Methods: The murine CXCR4 gene was inserted into retroviral vector, pMP71. Murine T cells were transduced with CXCR4 or control vector and tested for homing in vitro to CXCL12 through chemotaxis assays. In vivo imaging of the putative endosteal bone marrow (BM) niche was performed by multiphoton imaging through cranial frontal bones in osteoblast (collagen 1-α-GFP) reporter mice. In vivo trafficking, competitive transfer and memory recall experiments were performed following transfer of transduced T cells to syngeneic, sub-lethally irradiated mice. Anti-tumour reactivity of CXCR4-transduced T cells was tested in models of allogeneic BM transplantation (BMT). Results: CXCR4-transduced T cells demonstrated enhanced migration towards CXCL12 in vitro. No differences in viability, phenotype or function were observed in CXCR4-transduced versus control T cells in the presence or absence of CXCL12. In competitive assays, CXCR4-transduced CD8 T cells demonstrated a 2-fold greater capacity than controls to home to the BM by 24h after transfer to sub-lethally-irradiated recipients. Multiphoton imaging through cranial frontal bones indicated that fluorescently labelled CXCR4-transduced T cells were closer than control cells to the endosteum (13 μm versus 17 μm, p<0.01). By 14 days, the numbers of CXCR4-transduced CD8 T cells in the BM were 15-fold greater than controls. To test immunity to model antigen, CXCR4 or control vector-transduced OT-1 TCR-transgenic CD8 cells were transferred to sub-lethally irradiated mice before challenge with OVA peptide-loaded dendritic cells. Pre-vaccination, CXCR4-transduced OT-1 cells demonstrated greater engraftment than controls in the BM and spleen. Seven days following vaccination, CXCR4 OT-1 cells demonstrated a greater capacity than control cells to generate IFN-γ to OVA-peptide. Four weeks following vaccination, CXCR4-transduced CD8 T cells showed increased frequencies of cells with a CD44highIL-7Rαhigh memory phenotype than controls, with a greater proportion of cells undergoing proliferation as evaluated by BrdU incorporation. To test T cell immunity against a tumor that exploits the CXCR4-CXCL12 axis to recruit regulatory T cells, B6 BM and CXCR4- or control transduced B6 T cells were transferred to irradiated BALB/c recipients given A20 tumor. Tumor growth was delayed to a greater extent following transfer of CXCR4-compared to control-transduced donor T cells. Conclusion: Over-expression of CXCR4 in CD8 T cells potentiates engraftment, initial effector function and generation of memory cells. Disclosures: Stauss: Cell Medica: Scientific Advisor Other.
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Tian, He, Liyu Wang, Yu Liu, Yalong Wang, Yujia Zheng, Tao Fan, Bo Zheng, et al. "Bioinformatics Analyses Reveals a Comprehensive Landscape of CXC Chemokine Family Functions in Non-Small Cell Lung Cancer." BioMed Research International 2021 (January 25, 2021): 1–34. http://dx.doi.org/10.1155/2021/6686158.
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Backgrounds. Lung cancer is a major source of tumor-related death each year with non-small cell lung cancer (NSCLC) being a prevalent subtype. The metastasis from NSCLC to the brain usually imposes many neuron disorders. Previous studies have suggested that communications among cancer cells and interstitial cells are essential in tumorigenesis and are influenced by chemokines. In the tumor microenvironment, CXC chemokines can participate in the shifting of immune cells and manage tumor cell condition, thus affecting the progression of cancer and patient destinies. However, the expression and values of CXC chemokine family in NSCLC have not been systematically illustrated using public databases. Methods. UALCAN, STRING, ONCOMINE, GeneMANIA, cBioPortal, GEPIA, TISIDB, TRRUST, TIMER, Kaplan-Meier Plotter, and R software were utilized in this study. Results. Based on the TIMER and UACLCAN databases, in LUAD patients, the expression levels of CXCL10, CXCL13, and CXCL14 were significantly elevated while the transcriptional levels of CXCL2/3/4/7/12/16 were significantly reduced; in LUSC patients, the expression levels of CXCL6/10/13/14 were significantly elevated while the expression levels of CXCL2/3/4/5/7/11/12/16/17 were significantly reduced. We found remarkable relevance between the pathological stages of LUAD patients and the expressions of CXCL8 (positive) and CXCL17 (negative). Similarly, there are significant correlations between the pathological stages of LUSC patients and the expressions of CXCL1/2/6/17. In LUAD, patients with low expression levels of CXCL1/4/7/8 and patients with high expression levels of CXCL12/14/16 were associated with a significantly better prognosis. But in LUSC, all correlations between chemokines and prognosis are statistically insignificant. Pairwise expression correlation analysis among CXC chemokines shows that there are 7 significant correlations (between CXCL1 and CXCL2, between CXCL1 and CXCL3, between CXCL1 and CXCL8, between CXCL2 and CXCL3, between CXCL4 and CXCL7, between CXCL9 and CXCL10, and between CXCL9 and CXCL11) in LUAD and 4 significant correlations (between CXCL1 and CXCL8, between CXCL2 and CXCL3, between CXCL4 and CXCL7, and between CXCL10 and CXCL11) in LUSC. Significant correlations between the expressions of CXC chemokines and the infiltration of six common types of immune cells were also discovered in both LUAD and LUSC. Conclusions. We provided a comprehensive landscape of the CXC chemokine family in LUAD and LUSC using the bioinformatics method and found differences between LUSC and LUAD in the field of CXC chemokines. Our study may help validate and identify known novel immunotherapeutic targets and prognostic biomarkers.
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Ferretti, Elisa, Vito Pistoia, and Anna Corcione. "Role of Fractalkine/CX3CL1 and Its Receptor in the Pathogenesis of Inflammatory and Malignant Diseases with Emphasis on B Cell Malignancies." Mediators of Inflammation 2014 (2014): 1–10. http://dx.doi.org/10.1155/2014/480941.
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Fractalkine/CX3CL1, the only member of the CX3C chemokine family, exists as a membrane-anchored molecule as well as in soluble form, each mediating different biological activities. It is constitutively expressed in many hematopoietic and nonhematopoietic tissues such as endothelial and epithelial cells, lymphocytes, neurons, microglial osteoblasts. The biological activities of CX3CL1 are mediated by CX3CR1, that is expressed on different cell types such as NK cells, CD14+monocytes, cytotoxic effector T cells, B cells, neurons, microglia, smooth muscle cells, and tumor cells. The CX3CL1/CX3CR1 axis is involved in the pathogenesis of several inflammatory cancer including various B cell malignancies. In tumors the interaction between cancer cells and cellular microenvironment creates a context that may promote tumor growth, increase tumor survival, and facilitate metastasis. Therefore the role of the CX3CL1/CX3CR1 has attracted interest as to the development of potential therapeutic approaches. Here we review the different effects of the CX3CL1/CX3CR1 axis in several inflammatory and neurodegenerative diseases and in cancer, with emphasis on human B cell lymphomas.
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Asai, Hiroaki, Hiroshi Fujiwara, Toshiki Ochi, Jun An, Toshiaki Shirakata, Kozo Nagai, Yukihiro Miyazaki, et al. "Forced Expression of CC Chemokine Receptor 2 Enhances Anti-Cancer Reactivity Mediated by T Lymphocytes Beforehand Redirected Toward WT1 Inside the Tumor Microenvironment." Blood 118, no. 21 (November 18, 2011): 2059. http://dx.doi.org/10.1182/blood.v118.21.2059.2059.
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Abstract Abstract 2059 Background & Purpose: Redirected T-cell based adoptive therapy using cancer antigen-specific T-cell receptor (TCR) gene transfer has proven promise, however its clinical efficacy still remains unsatisfactory. The less accumulation in number of infused redirected T cells at the local tumor site is one of the causes. In order to accumulate those tumor-responsive T cells inside tumor microenvironment, chemokine produced by tumor cells and/or tumor associated cells is an attractive target. In this study, we examined the feasibility of CC chemokine receptor 2 (CCR2) gene transfer into T cells beforehand redirected toward WT1 in order to enhance the anti-cancer reactivity, both in vitro and in vivo. Methods: HLA-A*24:02-restricted and WT1235–243-specific TCR-a/b genes were introduced into normal CD8+ T cells using our novel retroviral TCR-gene expression vector encompassing silencers for endogenous TCRs (WT1-si-TCR vector). mRNA expression of total 11 chemokines expressed by 10 human lung cancer cell lines was examined using QRT-PCR, then CCL2 (variably produced in 7 out of 10 examined cell lines) and the small lung cancer cell line, LK79 which abundantly produced CCL2 was chosen for the proof of concept. Cloned CCR2 gene was retrovirally introduced into Jurkat cells, Jurkat/MA cells and normal CD8+ T cells similarly redirected beforehand using WT1-siTCR vector. Introduced CCR2 was validated using flow cytometer and transwell experiments. Cytotoxicity was examined using standard 51chromium release assay. Cooperative functionality composed of CCL2-directinality and WT1-specific antitumor cytotoxicity mediated by those double gene transfectants was examined in vitro; values of LDH released from destroyed LK79 cells in the bottom well by migrated double gene transduced CD8+ T cells from the upper well were measured. Antitumor reactivity in vivo was assessed using xenograft mouse model using luciferase-transduced LK79 cells (LK79-luc). Direct effect of CCL2 ligation on WT1-TCR signaling in double gene transfectant was assessed using luciferase assay with double gene transduced TCR− Jurkat/MA cell line, which stably expresses hCD8a and NFAT-luciferase reporter genes (Jurkat/MA/CD8a/luc; kindly provided by Prof. Erik Hooijberg, Netherlands). Results: CCL2 sensitivity was successfully introduced by CCR2 gene transfer; CCR2 transduced Jurkat successfully directed toward CCL2 producing cell line, LK79 cells. CCR2 gene transduction did not impede WT1-specific cytotoxicity mediated by CD8+ T cells beforehand redirected using WT1-siTCR gene transfer, rather double gene transduction cooperatively endowed those transfectants with CCL2 sensitivity and WT1-specific cytotoxicity against LK79 cells. Furthermore, in vivo assay using xenograft mouse model, growth of subcutaneously inoculated LK79-luc cells was more efficiently suppressed by those double gene transduced CD8+ T cells than WT1-siTCR single gene trnasfectants, in particular, immediately after adoptive transfer. Finally, CCL2 synergistically enhanced the magnitude of cognate peptide evoked WT1-specific TCR signaling in a dose dependent manner. Even without WT1 peptide ligation, such TCR signaling was similarly evoked by CCL2 to some extent. Conclusion: In this study, our results demonstrate that forced expression of CCR2 on CTL beforehand redirected toward WT1 enhanced its anti-cancer reactivity both in vitro and in vivo. This in vivo enhancement of antitumor reactivity may be caused by increased number of effector cells and enhanced WT1-TCR signaling generated both by CCL2 in the local tumor microenvironment. Although further studies are warranted, CCR2 gene transfer into redirected WT1-specific tumor-reactive CTL may be feasible for the treatment of human cancers. Disclosures: No relevant conflicts of interest to declare.
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Monsalve, F. A., A. Rojas, I. Gonzalez, R. Perez, C. Añasco, J. Romero, P. Araya, L. S. Santos, and F. Delgado-Lopez. "RID: Evaluation of the Possible Inhibiting Effect of the Proinflammatory Signaling Induced by TNF-α through NF-κβ and AP-1 in Two Cell Lines of Breast Cancer." Mediators of Inflammation 2020 (June 22, 2020): 1–8. http://dx.doi.org/10.1155/2020/2707635.
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Receptor internalization and degradation (RID), is a transmembrane protein coded within the E3 region expression cassette of adenoviruses. RID downregulates the cell surface expression of epidermal growth factor receptor (EGFR), tumor necrosis factor receptor (TNFR), and apoptosis antigen 1 (FAS), causing a reduction of the effects of their respective ligands. In addition, RID inhibits apoptosis by decreasing the secretion of TNF-related apoptosis-inducing ligand (TRAIL) by normal tissue cells. In this article, we report that RID inhibited chemokine expression in human breast cancer cell line MDA-MB-231 but showed no effect in cell line MCF7. These dissimilar results may be due to the different molecular and functional properties of both cell lines. Therefore, it is necessary to replicate this study in other breast cancer cell models.
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Jorapur, Aparna, Lisa A. Marshall, Scott Jacobson, Mengshu Xu, Sachie Marubayashi, Mikhail Zibinsky, Dennis X. Hu, et al. "EBV+ tumors exploit tumor cell-intrinsic and -extrinsic mechanisms to produce regulatory T cell-recruiting chemokines CCL17 and CCL22." PLOS Pathogens 18, no. 1 (January 13, 2022): e1010200. http://dx.doi.org/10.1371/journal.ppat.1010200.
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The Epstein-Barr Virus (EBV) is involved in the etiology of multiple hematologic and epithelial human cancers. EBV+ tumors employ multiple immune escape mechanisms, including the recruitment of immunosuppressive regulatory T cells (Treg). Here, we show some EBV+ tumor cells express high levels of the chemokines CCL17 and CCL22 both in vitro and in vivo and that this expression mirrors the expression levels of expression of the EBV LMP1 gene in vitro. Patient samples from lymphoblastic (Hodgkin lymphoma) and epithelial (nasopharyngeal carcinoma; NPC) EBV+ tumors revealed CCL17 and CCL22 expression of both tumor cell-intrinsic and -extrinsic origin, depending on tumor type. NPCs grown as mouse xenografts likewise showed both mechanisms of chemokine production. Single cell RNA-sequencing revealed in vivo tumor cell-intrinsic CCL17 and CCL22 expression combined with expression from infiltrating classical resident and migratory dendritic cells in a CT26 colon cancer mouse tumor engineered to express LMP1. These data suggest that EBV-driven tumors employ dual mechanisms for CCL17 and CCL22 production. Importantly, both in vitro and in vivo Treg migration was effectively blocked by a novel, small molecule antagonist of CCR4, CCR4-351. Antagonism of the CCR4 receptor may thus be an effective means of activating the immune response against a wide spectrum of EBV+ tumors.
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Hayes, A. J., P. Burgoyne, R. Cooper, H. Johnsson, G. J. Graham, and J. Campbell. "Improving the function of NK cells in an anti-tumour model using fluorescent-based chemokine sorting." Cytotherapy 22, no. 5 (May 2020): S125—S126. http://dx.doi.org/10.1016/j.jcyt.2020.03.238.
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Roderburg, Christoph, Simon Labuhn, Jan Bednarsch, Sven A. Lang, Anne T. Schneider, Linda Hammerich, Mihael Vucur, et al. "Elevated Serum Levels of CCL23 Are Associated with Poor Outcome after Resection of Biliary Tract Cancer." Mediators of Inflammation 2022 (December 1, 2022): 1–9. http://dx.doi.org/10.1155/2022/6195004.
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Background. Surgical tumor resection is the only potentially curative treatment option for patients with biliary tract cancer (BTC). However, 5-year survival rates are still below 50% mainly due to tumor recurrence. The preoperative identification of ideal surgical candidates has remained a major challenge and easily accessible algorithms including parameters of the individual tumor biology are missing. Chemokine (C-C motif) ligand 23 (CCl23) has been associated with tumor progression in hepatocellular carcinoma (HCC), but its role in the context of BTC is largely unknown. Here, we evaluated circulating levels of CCL23 as potential diagnostic and prognostic biomarker in patients with resectable BTC. Methods. CCl23 serum levels were analyzed by multiplex immunoassay in a cohort of 119 BTC patients receiving surgical tumor resection as well as 50 healthy control samples and 11 patients with primary sclerosing cholangitis (PSC). Results. Baseline serum CCL23 levels were significantly elevated in BTC patients compared to PSC patients as well as healthy controls. CCL23 increased the diagnostic sensitivity and specificity of established tumor markers including CA19-9 and correlated with patients’ age and makers of systemic inflammation. Elevated preoperative CCL23 levels were associated with a significantly impaired postoperative outcome. BTC patients with a preoperative CCL23 level above the optimal prognostic cut-off value of 702.4 pg/ml showed a median OS of only 110 days compared to 501 days for patients with low initial CCL23 levels. The prognostic value of circulating CCL23 was confirmed in Cox-regression analysis. Conclusion. Serum levels of CCL23 are elevated in patients with BTC, and high preoperative CCL23 levels were associated with an impaired postoperative survival. CCL23 serum levels could help to identify the ideal surgical candidates for BTC resection in the future.
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Bakker, Jeroen, Maurice Habraken, John Dulos, Yu-Tzu Tai, Andrea Van Elsas, Paul Vink, and Hans Eenennaam. "Bion-1301 Blocks APRIL-Induced Anti-Apoptotic Signaling, Immune Suppressive Phenotype, and Chemokine Production Associated with Multiple Myeloma." Blood 132, Supplement 1 (November 29, 2018): 1908. http://dx.doi.org/10.1182/blood-2018-99-117726.
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Abstract A proliferation-inducing ligand (APRIL) is produced by multiple accessory and myeloid cells in the bone marrow niche. Through binding to its receptors B-cell maturation antigen (BCMA) and transmembrane activator and CAML interactor (TACI), APRIL plays an important role in the development and maintenance of cells derived from the B cell lineage. Both APRIL and its receptors have been identified as promotors of multiple myeloma (MM), a disease that is characterized by malignant proliferation of plasma cells in the bone marrow. We have shown that BION-1301, a first-in-class APRIL-targeting humanized antibody, blocks APRIL-induced effects on MM cell survival and the tumor microenvironment (TME). Despite recent approval of new therapies for MM, this type of cancer remains incurable as patients relapse and eventually become refractory to the current therapeutic regimens. We hypothesize that the presence of high levels of APRIL in the bone marrow of patients with MM establishes a protected environment favoring tumor cell survival and proliferation. The effects of APRIL were studied on tumor cell lines alone or in co-culture with osteoclasts, which are thought to produce APRIL in the bone marrow niche. We further hypothesize that engaging APRIL with BION-1301 sensitizes MM cells for other MM-targeting therapeutic agents. First, stimulation of MM cells with APRIL led to rapid phosphorylation of proteins in the NFκB pathway, that was completely blocked by the BION-1301 parental antibody hAPRIL.01A. In addition, by validating expression of known NFκB target genes, APRIL appears to protect MM cells from drug-induced toxicity by upregulation of anti-apoptotic genes (e.g. MCL-1), since APRIL enhanced survival of MM cells that were treated with anti-MM drugs, such as dexamethasone. Importantly, addition of hAPRIL.01A blocked this pro-survival effect, highlighting the potential of BION-1301 to enhance MM sensitivity towards MM-targeting agents. We confirmed the immune suppressive potential of APRIL by showing that APRIL upregulates known immunosuppressive proteins such as IL-10 and PD-L1, indicating that BION-1301 could increase sensitivity to therapies such as daratumumab that depend on the immune system. Finally, in vitro APRIL increased secretion of the chemokines MIP-1α and MIP-1β by MM cell lines, which are known to stimulate osteoclast differentiation and activation. This suggests a positive feedback loop in which APRIL, produced mainly by osteoclasts in the bone marrow, induces chemokine production by MM cells, and these chemokines in turn stimulate osteoclasts. Importantly, when hAPRIL.01A is added to block APRIL, chemokine production drops, indicating that in addition to sensitizing MM tumor cells for drug treatment, BION-1301 also suppresses osteoclast activity. Altogether, we demonstrate in vitro that APRIL induces anti-apoptotic signaling, triggers expression of an immune suppressive phenotype, and could potentially modulate the tumor microenvironment through the production of key chemokines. Blocking APRIL with BION-1301 may dampen these effects, illustrating the potential of BION-1301, as a therapeutic agent for MM, particularly in combination therapies. BION-1301 is currently in a phase 1 clinical trial for MM. Disclosures Bakker: Aduro Biotech: Employment. Habraken:Aduro Biotech: Employment. Dulos:Aduro Biotech: Employment. Van Elsas:Aduro Biotech Europe: Employment. Vink:Aduro Biotech Europe: Employment. Eenennaam:Aduro Biotech Europe: Employment, Equity Ownership.
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Scortegagna, Marzia, Christophe Cataisson, Rebecca J. Martin, Daniel J. Hicklin, Robert D. Schreiber, Stuart H. Yuspa, and Jeffrey M. Arbeit. "HIF-1α regulates epithelial inflammation by cell autonomous NFκB activation and paracrine stromal remodeling." Blood 111, no. 7 (April 1, 2008): 3343–54. http://dx.doi.org/10.1182/blood-2007-10-115758.
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AbstractHypoxia inducible factor-1 (HIF-1) is a master regulatory transcription factor controlling multiple cell-autonomous and non–cell-autonomous processes, such as metabolism, angiogenesis, matrix invasion, and cancer metastasis. Here we used a new line of transgenic mice with constitutive gain of HIF-1 function in basal keratinocytes and demonstrated a signaling pathway from HIF-1 to nuclear factor κ B (NFκB) activation to enhanced epithelial chemokine and cytokine elaboration. This pathway was responsible for a phenotypically silent accumulation of stromal inflammatory cells and a marked inflammatory hypersensitivity to a single 12-O-tetradecanoylphorbol-13-acetate (TPA) challenge. HIF-1–induced NFκB activation was composed of 2 elements, IκB hyperphosphorylation and phosphorylation of Ser276 on p65, enhancing p65 nuclear localization and transcriptional activity, respectively. NFκB transcriptional targets macrophage inflammatory protein-2 (MIP-2/CXCL2/3), keratinocyte chemokine (KC/CXCL1), and tumor necrosis factor [alfa] (TNFα) were constitutively up-regulated and further increased after TPA challenge both in cultured keratinocytes and in transgenic mice. Whole animal KC, MIP-2, or TNFα immunodepletion each abrogated TPA-induced inflammation, whereas blockade of either VEGF or placenta growth factor (PlGF) signaling did not affect transgenic inflammatory hyper-responsiveness. Thus, epithelial HIF-1 gain of function remodels the local environment by cell-autonomous NFκB-mediated chemokine and cytokine secretion, which may be another mechanism by which HIF-1 facilitates either inflammatory diseases or malignant progression.
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Burger, Jan A., and Thomas J. Kipps. "CXCR4: a key receptor in the crosstalk between tumor cells and their microenvironment." Blood 107, no. 5 (March 1, 2006): 1761–67. http://dx.doi.org/10.1182/blood-2005-08-3182.
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Signals from the microenvironment have a profound influence on the maintenance and/or progression of hematopoietic and epithelial cancers. Mesenchymal or marrow-derived stromal cells, which constitute a large proportion of the non-neoplastic cells within the tumor microenvironment, constitutively secrete the chemokine stromal cell-derived factor-1 (SDF-1/CXCL12). CXCL12 secretion by stromal cells attracts cancer cells, acting through its cognate receptor, CXCR4, which is expressed by both hematopoietic and nonhematopoietic tumor cells. CXCR4 promotes tumor progression by direct and indirect mechanisms. First, CXCR4 is essential for metastatic spread to organs where CXCL12 is expressed, and thereby allows tumor cells to access cellular niches, such as the marrow, that favor tumor-cell survival and growth. Second, stromal-derived CXCL12 itself can stimulate survival and growth of neoplastic cells in a paracrine fashion. Third, CXCL12 can promote tumor angiogenesis by attracting endothelial cells to the tumor microenvironment. CXCR4 expression is a prognostic marker in various types of cancer, such as acute myelogenous leukemia or breast carcinoma. Promising results in preclinical tumor models indicate that CXCR4 antagonists may have antitumor activity in patients with various malignancies. Collectively, these observations reveal that CXCR4 is an important molecule involved in the spread and progression of a variety of different tumors. As such, CXCR4 antagonists, although initially developed for treatment of AIDS, actually may become effective agents for the treatment of neoplastic disease.
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Lim, F., D. Guo, J. Chen, A. Law, Z. Y. Poon, A. Cheung, J. C. Tan, et al. "POS0417 EXOGENOUS CXCL5 RESTORES ENDOGENOUS BLOOD-TISSUE CHEMOKINE GRADIENT TO IMPROVE SURVIVAL IN MURINE LUPUS." Annals of the Rheumatic Diseases 80, Suppl 1 (May 19, 2021): 437.2–438. http://dx.doi.org/10.1136/annrheumdis-2021-eular.2262.
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Background:Systemic lupus erythematosus (SLE) is a multi-organ autoimmune disease that is potentially fatal. There is an unmet need to improve current therapies. In patients with SLE, we observed that serum CXCL5 levels were significantly lower than healthy control subjects and negatively correlated with disease activity(1-9).Objectives:The aim of this study is to elucidate the effect of supplemental serum CXCL5 in abrogating the pathological processes of SLE.Methods:Ten doses of exogenous CXCL5 (3µg/kg) was administered to 16-week-old Faslpr mice weekly by intravenous injection. Mice were monitored for 10 weeks. Splenic immune profile was measured by flow cytometry. Circulating cytokine and immunoglobulin profile were detected by Luminex technology. Renal function was evaluated by urinary spot albumin creatinine ratio. In situ renal immune cell infiltration and complement 3 deposition were detected by Haematoxylin and Eosin (H&E) and immunohistochemistry staining. The molecular pathways involved were examined by RNA sequencing.Results:In Faslpr mice, intravenous administration of exogenous CXCL5 significantly improved mouse survival with concomitant reduction of autoantibody secretion, proteinuria, complement 3 deposition, neutrophil infiltration and lupus nephritis classes. Through evaluating the changes of immune profile, cytokine profile and molecular pathways, we found that intravenous CXCL5 reduced inflammation via an orchestral effect of regulating neutrophil trafficking and modulating helper T cell-mediated immune response. Pharmacokinetic and real-time Polymerase Chain Reaction studies further demonstrated that this orchestration was triggered by a cascade reaction - restoring vascular under-expressed CXCL5 by an exogenous stimulation, re-establishing the normal serum levels of endogenous CXCL5 and reverting the CXCL5 chemokine gradient between inflamed tissues and blood circulation.Conclusion:Managing the dysregulation of CXCL5 by exogenous supplement may provide a new option for SLE therapy.References:[1]Dufies M, Grytsai O, Ronco C, et al. New CXCR1/CXCR2 inhibitors represent an effective treatment for kidney or head and neck cancers sensitive or refractory to reference treatments. Theranostics. 2019;9(18):5332-5346. doi:10.7150/thno.34681[2]Yildirim K, Colak E, Aktimur R, et al. Clinical Value of CXCL5 for Determining of Colorectal Cancer. Asian Pac J Cancer Prev. Sep 26 2018;19(9):2481-2484. doi:10.22034/apjcp.2018.19.9.2481[3]Wu K, Yu S, Liu Q, Bai X, Zheng X. The clinical significance of CXCL5 in non-small cell lung cancer. Onco Targets Ther. 2017;10:5561-5573. doi:10.2147/ott.s148772[4]Zhao J, Ou B, Han D, et al. Tumor-derived CXCL5 promotes human colorectal cancer metastasis through activation of the ERK/Elk-1/Snail and AKT/GSK3beta/beta-catenin pathways. Mol Cancer. Mar 29 2017;16(1):70. doi:10.1186/s12943-017-0629-4[5]Han KQ, Han H, He XQ, et al. Chemokine CXCL1 may serve as a potential molecular target for hepatocellular carcinoma. Cancer Med. Oct 2016;5(10):2861-2871. doi:10.1002/cam4.843[6]Pappa CA, Tsirakis G, Kanellou P, et al. Monitoring serum levels ELR+ CXC chemokines and the relationship between microvessel density and angiogenic growth factors in multiple myeloma. Cytokine. Dec 2011;56(3):616-20. doi:10.1016/j.cyto.2011.08.034[7]Zhang L, Li H, Ge C, et al. CXCL3 contributes to CD133(+) CSCs maintenance and forms a positive feedback regulation loop with CD133 in HCC via Erk1/2 phosphorylation. Sci Rep. Jun 3 2016;6:27426. doi:10.1038/srep27426[8]Matsubara J, Honda K, Ono M, et al. Reduced plasma level of CXC chemokine ligand 7 in patients with pancreatic cancer. Cancer Epidemiol Biomarkers Prev. Jan 2011;20(1):160-71. doi:10.1158/1055- 9965.epi-10-0397[9]Ma Y, Ren Y, Dai ZJ, Wu CJ, Ji YH, Xu J. IL-6, IL-8 and TNF-alpha levels correlate with disease stage in breast cancer patients. Adv Clin Exp Med. May-Jun 2017;26(3):421-426. doi:10.17219/acem/62120Disclosure of Interests:None declared
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Weitzenfeld, Polina, Olga Kossover, Cindy Körner, Tsipi Meshel, Stefan Wiemann, Dror Seliktar, Daniel F. Legler, and Adit Ben-Baruch. "Chemokine axes in breast cancer: factors of the tumor microenvironment reshape the CCR7-driven metastatic spread of luminal-A breast tumors." Journal of Leukocyte Biology 99, no. 6 (March 2, 2016): 1009–25. http://dx.doi.org/10.1189/jlb.3ma0815-373r.
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Brandao, Joana G., Joao T. Barata, Raquel Nunes, Lee M. Nadler, and Angelo A. Cardoso. "Crosstalk between Breast Cancer Cells and Bone Marrow Endothelium Require the Engagement of PI3K/AKT Signaling." Blood 104, no. 11 (November 16, 2004): 1299. http://dx.doi.org/10.1182/blood.v104.11.1299.1299.
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Abstract The presence of breast cancer cells in the patient’s bone marrow (BM) at diagnosis is associated with resistance to treatment, disease relapse and poor prognosis. Identification of the factors implicated in the homing, survival and latency of breast cancer cells in the BM should contribute to the design of more efficient therapeutic strategies for breast cancer. There is evidence that breast cancer can recruit endothelial progenitors from the BM. Also, other epithelial tumors seem to preferentially adhere to BM endothelial cells. Therefore, we hypothesized that BM endothelium may play a significant role in the biology of breast cancer cells residing in the BM. Co-cultures in Matrigel showed that breast cancer cells interact with BM endothelium to form heterotypic multicellular networks. Moreover, breast cancer cells migrate towards BM endothelium assembled as capillary-like structures, but not to structures of BM mesenchymal stem cells or BM stroma. This migration was abrogated by pertussis toxin-mediated blockade of chemokine receptor signaling, suggesting the involvement of endothelium-secreted chemokine(s). We then evaluated the impact of breast cancer cells in the survival and proliferation of BM endothelium. All breast cancer lines tested (n=4) promoted the proliferation of BM-derived endothelial cells. This effect is mediated through the engagement of the PI3K/Akt pathway (phosphorylation of Akt at Ser437 and Thr308, and activation of its downstream substrates GSK3β, PRAS-40 and FKHRL1) since its specific blockade abrogated the stimulatory effects of breast cancer on BM endothelium. We next determined whether, reciprocally, BM endothelium impacts on breast cancer cell survival. These experiments were performed in serum-free media to enhance dependency of breast cancer cells from microenvironmental stimuli. In all cases tested, BM endothelium promoted survival/proliferation of breast cancer cells. This stimulation was accompanied by the engagement of the PI3K/Akt pathway in breast cancer cells and, in three of the four lines, the phosphorylation of Erk1/2. These effects were also observed for breast cancer cells that showed constitutive activation of Akt (MCF-7 and ZR-75-1 cells). Specific blockade of PI3K/Akt abrogated the BM endothelium-promoted survival of breast cancer cells, thus demonstrating the critical role of this pathway. These studies show that crosstalk between BM endothelial cells and breast cancer cells may impact on the survival of both cell types. These findings provide new light on the mechanisms that may facilitate the development of a tumor-permissive BM microenvironment in breast cancer, and the creation of breast cancer-supporting BM niches. Importantly, this study implicates BM endothelium as a therapeutic target in breast cancer and suggest that blockade of PI3K/Akt may impact the outcome of patients with metastatic breast cancer.
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Gajewski, Thomas. "Innate Immune Sensing in Anti-Tumor Immunity and Cancer Immunotherapy." Blood 128, no. 22 (December 2, 2016): SCI—27—SCI—27. http://dx.doi.org/10.1182/blood.v128.22.sci-27.sci-27.
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Abstract Most cancers express tumor antigens that can be recognized by T cells of the host. The fact that cancers that become clinically relevant grow, nonetheless implies that immune escape must occur to allow cancer outgrowth. We have observed two major subsets of human melanoma metastases based on gene expression profiling and confirmatory assays. One subgroup of patients has a T cell-inflamed phenotype that includes expression of chemokines, T cell markers, and a type I interferon (IFN) signature. In contrast, the other major subset lacks this phenotype and appears to display immune "exclusion". The mechanisms of immune escape are likely distinct in these two phenotypes, and therefore the optimal immunotherapeutic interventions necessary to promote clinical responses may be different. The T cell-inflamed tumor microenvironment subset shows the highest expression of negative regulatory factors, including PD-L1, IDO, and FoxP3+ Tregs, and evidence for T cell-intrinsic anergy has also emerged aided by a recently defined functional role of EGR2. In addition, the mechanism of induction of these inhibitory mechanisms has been elucidated-PD-L1 and IDO are induced by IFN-g, and Tregs are largely recruited by the chemokine CCL22, both being produced by activated CD8+ effector T cells. Preclinical experiments have confirmed a critical role for each of these mechanisms in limiting anti-tumor T cell efficacy in vivo, giving candidate treatment strategies for translation back into the clinic. These include anti-PD-1/PD-L1 mAbs, IDO inhibitors, and approaches to deplete CD25+ Tregs and/or reverse anergy. The presence of multiple inhibitory mechanisms in the same tumor microenvironment argues that combination therapies may be advantageous. Preclinical data have indicated synergy between anti-CTLA-4 +/- anti-PD-L1 +/- IDO inhibition. Clinical translation of multiple combination immunotherapies is promising and ongoing. In contrast to the T cell-inflamed melanomas, a new paradigm may be needed to promote de novo inflammation in cases of the non-T cell-infiltrated tumor microenvironment. Natural innate immune sensing of tumors appears to occur via the host STING pathway, type I IFN production, and cross-priming of T cells via CD8a+ dendritic cells. New strategies are being developed to engage or mimic this pathway as a therapeutic endeavor, including STING agonists. A phase I study of intratumoral injection of the first STING agonist is ongoing. As an environmental variable, recent work has implicated the commensal microbiota as a regulator of DC activation status and systemic anti-tumor immunity, and clinical analysis of microbiota sequencing in the context of checkpoint blockade is ongoing. Disclosures Gajewski: Evelo: Patents & Royalties: Patent application; Jounce: Consultancy; Merck: Consultancy, Research Funding; Aduro: Patents & Royalties: Patent application; Incyte: Consultancy, Research Funding; Celldex: Consultancy, Research Funding; BMS: Research Funding; Roche/Genentech: Consultancy, Research Funding; Bayer: Consultancy; Abbvie: Consultancy.
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Wong, Tina W., Denise K. Walters, Hirohito Kita, and Diane F. Jelinek. "Eosinophils in the Bone Marrow Microenvironment: Effects On Malignant Plasma Cell Biology." Blood 120, no. 21 (November 16, 2012): 2917. http://dx.doi.org/10.1182/blood.v120.21.2917.2917.
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Abstract Abstract 2917 Multiple myeloma (MM) is a cancer in the bone marrow (BM) characterized by the accumulation of transformed plasma cells (PCs). The pre-malignant form of the disease, monoclonal gammopathy of undetermined significance (MGUS), shares many of the genetic abnormalities found in MM, including chromosomal translocations, hyperdiploidy, and gene-specific mutations. Given this, we believe other factors within the tumor microenvironment must contribute to disease progression by influencing cell survival and/or proliferation. Eosinophils (Eos) are granulocytic leukocytes that are best known for their involvement in host immune defense and pathologic states such as allergy and asthma. Recently, they were also shown to play a role in the regulation of murine BM PC homeostasis via their secretion of IL-6 and APRIL. Murine BM PCs and Eos both express CXCR4 and are believed to home to CXCL12 expressing stromal cells (SCs) in the BM. The goal of this study, therefore, was to investigate whether Eos, or soluble mediators released by Eos, have biological activity on MM cells. Thus, it is possible that this type of innate immune cell may be present in the tumor microenvironment in MM patients to support disease progression. To our knowledge, a potential role for Eos in MM has not been previously studied. We began our studies by assessing whether Eos are co-localized with normal BM PCs and/or MM PCs. Immunofluorescence analysis of BM core biopsies from normal subjects revealed occasional colocalization of PCs with Eos. Similarly, MM biopsies showed regions of MM cell clusters with increased Eos density, suggesting possible biological interactions. However, we also observed regions of MM cell clusters that lack Eos, which could indicate the liberation of these transformed cells from the requirement of Eos for survival/proliferation. Next, using Eos isolated from human BM aspirates and a panel of disease-relevant human MM cell lines (HMCLs) extensively characterized in our laboratory, we aimed to verify that MM cells and Eos could both migrate toward the chemokine CXCL12. Our data showed that indeed the KAS-6/1, ANBL-6, DP-6, and KP-6 HMCLs and human BM Eos all migrated toward this chemokine. We then determined if Eos had biological activity towards MM cells as revealed by enhanced DNA synthesis. Consistent with our interpretation of the immunofluorescence stained sections, the proliferation of some, but not all, HMCLs was enhanced when cocultured with Eos isolated from either human BM or peripheral blood. To address whether contact between Eos and HMCLs was required for this phenomenon, we assessed HMCL proliferation upon treatment with Eos culture supernatant (SN). Our data suggest that the effect of Eos on the Eos-inducible HMCLs can be contact-independent as treatment of these HMCLs with Eos SN increased their proliferation. Similarly, proliferation of primary CD138+ MM cells was also enhanced when treated with Eos SN. Because BM PCs reside in niches that include support cells such as SCs and that proliferation of MM PCs is enhanced in the presence of SCs, we next questioned whether Eos can substitute for SCs in this niche or if Eos and SCs support PC survival/proliferation through different mechanisms. We observed that Eos and BM SCs together stimulated more HMCL proliferation than either cell type did alone, indicating the presence of non-redundant roles for the two cell types. Finally, we began to investigate the mechanism by which Eos enhance HMCL proliferation. In contrast to prior reports that murine Eos express IL-6, mRNA transcripts of IL-6, a known proliferation-inducing cytokine for MM cells, were not detected in human Eos. Moreover, analysis of the Eos SN showed an absence of IL-6. Neutralization of IL-6 in the HMCL-Eos coculture did not abolish the induced proliferation. Altogether, these data suggest that human Eos utilize a yet to be identified, IL-6-independent mechanism to support malignant PC proliferation. Taken together, our data show that Eos and MM cells can colocalize in the BM via their migration toward a common source of CXCL12, i.e. BM SCs, to create a niche that promotes tumor cell growth. Eos can enhance malignant PC proliferation via soluble products, although additional contact-dependent effects may exist as well and have not been explored. Additional studies are currently underway to further characterize the mechanism by which Eos may influence the biology of MM in the tumor microenvironment. Disclosures: No relevant conflicts of interest to declare.
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Wan, Tao, Xiangyang Zhou, Guoyou Chen, Huazhang An, Taoyong Chen, Weiping Zhang, Shuxun Liu, et al. "Novel heat shock protein Hsp70L1 activates dendritic cells and acts as a Th1 polarizing adjuvant." Blood 103, no. 5 (March 1, 2004): 1747–54. http://dx.doi.org/10.1182/blood-2003-08-2828.
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Abstract Heat shock proteins (HSPs) are reported to act as effective adjuvants to elicit anti-tumor and anti-infection immunity. Here, we report that Hsp70-like protein 1 (Hsp70L1), a novel HSP derived from human dendritic cells (DCs), has potent adjuvant effects that polarize responses toward Th1. With a calculated molecular weight of 54.8 kDa, Hsp70L1 is smaller in size than Hsp70 but resembles it both structurally and functionally. Hsp70L1 shares common receptors on DCs with Hsp70 and can interact with DCs, promoting DC maturation and stimulating secretion of the proinflammatory cytokines interleukin 12p70 (IL-12p70), IL-1β, tumor necrosis factor-α (TNF-α), and the chemokines IP-10, macrophage inflammatory protein-1α (MIP-1α), MIP-1β, and normal T cell expressed and secreted (RANTES). The induction of interferon-γ–inducible protein 10 (IP-10) secretion by Hsp70L1 is not shared by Hsp70, and other functional differences include more potent stimulation of DC IL-12p70, CC-chemokine, and CCR7 and CXCR4 expression by Hsp70L1. Immunization of mice with the hybrid peptide Hsp70L1-ovalbumin(OVA)257-264 induces an OVA257-264-specific Th1 response and cytotoxic T lymphocyte (CTL) that results in significant inhibition of E.G7-OVA tumor growth. The ability of Hsp70L1 to activate DCs indicates its potential as a novel adjuvant for use with peptide immunizations; the Hsp70L1 antigen peptide hybrid may serve as a more effective vaccine for the control of cancer and infectious diseases.
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Haining, W. Nicholas, Holger Kanzler, Jeffrey Davies, Linda Drury, Jeffrey Kutok, Thomas Brenn, Jill Angelosanto, et al. "A Novel Role for CpG Oligonucleotides in Tumor Immunotherapy: CpG-ODN Induce Targeted Chemokine-Induced Lymphocyte Migration to the Peripheral Tissues in Humans." Blood 110, no. 11 (November 16, 2007): 1791. http://dx.doi.org/10.1182/blood.v110.11.1791.1791.
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Abstract CpG ODN are being actively investigated as cancer vaccine adjuvants because they mature plasmacytoid dendritic cells (pDC) into potent antigen-presenting cells. In addition, TLR ligands induce a broad range of other immunologic effects in pDC including the secretion of interferon α (IFNa) and chemokines which alter lymphocyte migration. Whether these CpG-ODN driven TLR ligand signals enhance antigen specific Immunity and/or trafficking In humans Is presently unknown. We evaluated the efficacy of the CpG-ODN, 1018-ISS, as a vaccine adjuvant given with GM-CSF to induce T cell immunity in humans to the tumor antigen hTERT. Seventeen patients with advanced solid tumors were treated with 6 cycles of GM-CSF (x 3d), CpG-ODN (escalating from 3mg - 100mg × 1d) followed by a peptide vaccine (a CD8 epitope from hTERT), in a Phase I dose escalation study. Surprisingly, only one of seventeen patients showed a detectable hTERT-specific tetramer T cell response. However, the majority of patients developed marked peripheral blood (PB) lymphopenia after CpG-ODN. Time-course flow cytometry analysis of PB revealed that CD8, CD4, NK and B cell counts were all depressed immediately after CpG-ODN. The effect was transient, with normal counts returning after a week, suggesting that CpG-ODN induced alteration in cell migration rather than cell death. To find further evidence for altered migration we examined vaccine sites. Clinically, vaccine sites showed significant swelling/induration within hours of CpG-ODN administration, though none was dose-limiting. Immunohistochemistry of vaccine biopsies showed significant, perivascular accumulation of CD4 and CD8 T cells clustered around CD123+ pDC. Biopsies after CpG-ODN, but not after GM-CSF, showed a marked increase in expression of MxA, an interferon-inducible gene suggesting that the local activation of pDC with resultant IFNa secretion. qRT-PCR confirmed significant increases in a panel of IFNa-inducible genes in the PB after CpG-ODN, indicating a systemic effect of IFNa secretion. Lastly, we showed directly that CpG-ODN markedly increased the ability of purified pDC to induce T cell migration in an in vitro transwell assay, demonstrating that CpG-ODN stimulation of human pDC not only induces IFNa, but also other chemokines that are sufficient to chemoattract T cells. Our results show that CpG-ODN with GM-CSF may not be an effective adjuvant strategy for peptide tumor vaccines; but sequenced GM-CSF/CpG-ODN causes a chemokine response that effects T cell migration to the peripheral tissues. These findings suggest a role for CpG beyond that of a vaccine adjuvant as a mediator of lymphocyte migration, targeting immune responses to specific peripheral tissues. Therapeutic intratumoral GM-CSF/CpG-ODN injection could profoundly alter the local immunologic milieu, recruiting activated pDC and T cells to the tumor site, and tipping the balance towards an effective tumor-specific immune response.
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Corinaldesi, Giorgio, and Christian Corinaldesi. "Low Molecular Weight Heparin in Patients with Cancer: A New Option." Blood 112, no. 11 (November 16, 2008): 4058. http://dx.doi.org/10.1182/blood.v112.11.4058.4058.
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Abstract The use of heparin for venous thromboembolism, upper extremity deep vein thrombosis (DVT), septic thrombophlebitis, loss of central venous device access in patients with cancer is a standard practice; a new clinical evidence suggest that low molecular weight heparin (LMWHs) may prolong survival in patients with cancer and may have anti-neoplastic effects and anti-metastatic activity. We evaluated 74 patients with cancer (38 patients were allocated to enoxaparin 6000UI subcutaneously once a day, and 36 patients were allocated to placebo), the mean duration of follow-up was 12 months, platelet count were performed before the treatment, and once a month; in the event of thrombocytopenia < 50.000/ml or abnormal bleeding the treatment was stopped. The primary end points were overall survival, and metastasis progression. TAB:A Enoxaparin (n.38) Placebo (n.36) Age-years (range) 46–68 48–66 Sex (male/female) 20/18 20/16 Metastasis disease a) before 10 12 b) end-therapy 12 18 Type of cancer Breast cancer 8 8 Endometrial cancer 6 5 Gastric or esophageal 4/2 3/1 Colorectal cancer 6/2 8/2 Prostatic cancer 6 7 Urothelial 2 1 Lung 2 1 Death 3 8 Major bleeding 1 0 Minor bleeding 4 4 Allergic reaction 0 0 VTE 6 0 Concomitant anti-neoplastic therapy Chemotherapy 26 26 Radiotherapy 2 1 Combined 4 3 Hormonal 6 6 These data show that LMWHs reduce or attenuate metastasis at 12 month by 11.4%, and death by 8.8%, with a significant increase of median survival. Heparin have show to have direct antigrowth, antiangiogenesis, and antimetastatic effects, LMWHs minimize angiogenesis with the inhibition of VEGF and b-FGF, inhibit the adhesion of cancer cells to endothelium and the interaction mediated by tumor cells surface mucins and selectin, and they interfere with cancer biology; we can speculate that the binding of tumor growth to heparin have a crucial role in the modulation of activity of the high affinity receptors, it promotes receptors dimerization and activation, inhibits P and L-selectins and chemokine action (IL-8, Mip-1), blocks MMP, serin-protease and heparanase, decreases over-expression of TF and PAF, induces and increases apoptosis.
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Guo, Qiuchen, Michael W. Malloy, Harvey G. Roweth, Joseph E. Italiano, and Elisabeth Battinelli. "Platelets up-Regulate Tumor Cell Programmed Death-Ligand 1 through Epidermal Growth Factor Receptor Signal Transduction." Blood 138, Supplement 1 (November 5, 2021): 1006. http://dx.doi.org/10.1182/blood-2021-151339.
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Abstract Introduction: Programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) are important immune checkpoint proteins in cancer immunotherapy and targeted therapies against PD-L1 have significantly prolonged many patients' lives. Recently, high baseline platelet to lymphocyte ratio was reported to be associated with decreased patient response rate to immune checkpoint inhibition (ICI) therapies, including anti-PD-L1 therapy, suggesting the potential role of platelets in tumor immunity. Platelets express PD-L1 on their surface, and platelets binding to PD-L1 negative tumor cells can "decorate" tumor cells with PD-L1 and protect against T cell-mediated cytotoxicity. However, whether platelet can affect PD-L1 expression on tumor cells is still unknown. Methods: In this study, we designed platelet-tumor cell co-culture systems to investigate whether direct or indirect exposure to platelets affects tumor cell PD-L1 surface expression. Considering platelets can be artificially activated by commonly used cell culture medium, the co-culture was performed in platelet resuspension buffer (HEPES, NaCl, KCl, MgCl2, NaHCO3, Glucose, pH7.4) supplied with fetal bovine serum and L-glutamine. After 24 hours of co-culture, platelets were washed out and fresh culturing medium was added to tumor cells and cultured for another 24 hours. At the end of the experiments, tumor cells were harvested and the PD-L1 expression analyzed by flow cytometry and RT-qPCR. Results and discussion: Here we report that direct co-culture of platelets with either breast cancer cell line MDA-MB-468 or lung cancer cell line A549 increased tumor cell PD-L1 surface expression by up-regulating PD-L1 transcription. This platelet-induced tumor cell PD-L1 up-regulation can be partly reduced by pre-treating platelets with antiplatelet agents such as aspirin and ticagrelor, suggesting platelet activation contributes to platelet induced tumor cell PD-L1 up-regulation. The up-regulation of tumor cell PD-L1 by platelets was not due to abundant platelet cytokines such as C-C Motif Chemokine Ligand 5 (CCL5) and C-X-C motif chemokine 5 (CXCL5). However, both an epidermal growth factor (EGF) neutralizing antibody and cetuximab (EGFR neutralizing monoclonal antibody) decreased the platelet-induced increase in tumor cell PD-L1, suggesting that platelets initiate tumor cell PD-L1 transcription through the EGF signaling pathway. Our data indicate a novel function of platelets in tumor immunity and warrant further investigation to determine if targeting platelets offers a novel adjuvant approach to improve ICI therapy. Disclosures Italiano: Sierra Oncology: Consultancy; PlateletBio: Current holder of individual stocks in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Carrick Therapeutics: Consultancy.
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Xing, Qianwei, Huyang Xie, Bingye Zhu, Zhiwei Sun, and Yeqing Huang. "MiR-455-5p Suppresses the Progression of Prostate Cancer by Targeting CCR5." BioMed Research International 2019 (April 11, 2019): 1–8. http://dx.doi.org/10.1155/2019/6394784.
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Accumulated evidence indicates that miR-455-5p functions as tumor suppressor in the progression of various cancers. However, the mechanism through which miR-455-5p influences the tumorigenesis of human prostate cancer (PCa) remains undetermined. In this study, reanalysis of data obtained from the Memorial Sloan Kettering Cancer Center showed that miR-455-5p can be used as biomarker for PCa diagnosis and predictor of poor prognosis. Functional assays indicated that miR-455-5p overexpression could suppress cellular proliferation, inhibit tumor growth, and trigger apoptosis by activating and cleaving caspase 3. We experimentally verified that miR-455-5p negatively regulated the C–C motif chemokine receptor 5 (CCR5). Overall, our data demonstrate that miR-455-5p suppressed PCa cellular proliferation and induced cell apoptosis by downregulating CCR5. Thus, miR-455-5p may be considered a new therapeutic strategy for PCa.
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Carvalho, Maria Isabel, Isabel Pires, Justina Prada, and Felisbina L. Queiroga. "A Role for T-Lymphocytes in Human Breast Cancer and in Canine Mammary Tumors." BioMed Research International 2014 (2014): 1–11. http://dx.doi.org/10.1155/2014/130894.
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Chronic inflammation in the tumor microenvironment has a prominent role in carcinogenesis and benefits the proliferation and survival of malignant cells, promoting angiogenesis and metastasis. Mammary tumors are frequently infiltrated by a heterogeneous population of immune cells where T-lymphocytes have a great importance. Interestingly, similar inflammatory cell infiltrates, cytokine and chemokine expression in humans and canine mammary tumors were recently described. However, in both species, despite all the scientific evidences that appoint for a significant role of T-lymphocytes, a definitive conclusion concerning the effectiveness of T-cell dependent immune mechanisms has not been achieved yet. In the present review, we describe similarities between human breast cancer and canine mammary tumors regarding tumor T-lymphocyte infiltration, such as relationship of TILs and mammary tumors malignancy, association of ratio CD4+/ CD8+ T-cells with low survival rates, promotion of tumor progression by Th2 cells actions, and association of great amounts of Treg cells with poor prognostic factors. This apparent parallelism together with the fact that dogs develop spontaneous tumors in the context of a natural immune system highlight the dog as a possible useful biological model for studies in human breast cancer immunology.
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Knight, Robert J., Tracey A. O’Brien, Robert Lindeman, and Alla Dolnikov. "Mutant Ras-Expressing Fibroblasts Induce Expansion of Circulating Angio- and Lymphangiogenic Precursor Cells: Potential Role in Tumour Vascularisation." Blood 108, no. 11 (November 16, 2006): 1331. http://dx.doi.org/10.1182/blood.v108.11.1331.1331.
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Abstract Fibroblasts have a prominent role in the initiation, enlargement and metastasis of cancers. Their production of growth factors, chemokines and extracellular matrix facilitate the angiogenic recruitment of endothelial cells and pericytes. The oncogene Ras, known to be frequently mutated in many cancers, has also been shown to promote the expression of pro-angiogenic growth factors, chemokines and extracellular matrix components similar to those of fibroblasts. Here we show that mutant N-ras (N-rasm)/GFP - transduced NIH3T3 fibroblasts act to promote the ex vivo expansion of umbilical cord blood (UCB)-derived primitive endothelial progenitor cells through paracrine mechanisms. Biphasic expansion of both angiogenic and lymphangiogenic precursors was observed although they exhibited different dynamics in their expansion pattern. The first peak of expansion for both types of precursor cells was seen on day 10 with a 69-fold expansion of the CD34+VEGFR2+(endothelial) and a 23-fold expansion of CD34+VEGFR3+(lymphatic) cells co-cultured with media conditioned by N-rasm-transduced 3T3 cells. This compared to a 20-fold and 14-fold expansion respectively, in cells co-cultured with media conditioned by GFP (only)-transduced fibroblasts. Endothelial cell differentiation accounts for the dramatic reduction in the numbers of CD34+VEGFR2+ and CD34+VEGFR3+ precursor cells on day 14 with concomitant expansion of CD34−VEGFR2+ and CD34−VEGFR3+cells. The second peak for the expansion of endothelial precursor cells was seen on day 19 with a 214-fold expansion compared to 28-fold in the control cells. In addition, the expansion of CD14+ VEGFR2+ and CD14+VEGFR3+ cells was observed on days 14 and 19, the later correlated with the expansion of monocytic CD34−CD14+ cells promoted by N-rasm-transduced fibroblasts. The expanded monocytes appear to contribute to the expansion of endothelial and lymphatic precursor cells induced by N-rasm-transduced fibroblasts. We propose that the angiogenic factors secreted by mutant Ras-expressing fibroblasts in a tumour microenvironment promote tumour angiogenesis through the expansion of the circulated endothelial and lymphatic precursor cells. The recruitment of the expanded endothelial and lymphatic cells into the tumour’s vascular system is currently being investigated. We propose that targeting aberrant Ras signaling in tumour fibroblasts may represent an important target for cancer therapies.
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Yu, Yizhi, Xiaoling Luo, Shuxun Liu, Yuan Xie, and Xuetao Cao. "Intratumoral Expression of MIP-1b Induces Antitumor Responses in a Pre-Established Tumor Model through Chemoattracting T Cells and NK Cells." Blood 104, no. 11 (November 16, 2004): 5268. http://dx.doi.org/10.1182/blood.v104.11.5268.5268.
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Abstract Direct intratumoral introduction of therapeutic or regulatory genes is a developing technology with potential application for cancer gene therapy. Macrophage inflammatory protein-1 beta (MIP-1b) is a chemokine which can chemoattract immune cells such as T cells. In the present study, murine colorectal adenocarcinoma CT26 cells were transfected with a recombinant adenovirus (AdhMIP-1b) carrying the human MIP-1b gene. 24h post-transfection, hMIP-1b levels reached approximately 980 pg/ml in supernatants of 106 hMIP-1b-transfected CT26 cells. Moreover, the supernatants exhibited chemotactic activity for CD8+ T cells, CD4+ T cells, NK cells and immature DCs. Intratumoral injection of AdhMIP-1b significantly inhibited tumor growth and prolonged the survival time of tumor-bearing mice. Intratumoral hMIP-1b gene transfer also induced powerful tumor-specific CTL responses in vivo. The therapeutic effects of hMIP-1b gene therapy were greatly reduced following in vivo depletion of both CD4+ and CD8+ T cells, but were unaffected by depletion of single T cell subsets. Immune cell depletion experiments also revealed that NK cells played an important role in hMIP-1b-induced anti-tumor responses. These results suggest that intratumoral expression of hMIP-1b has the potential effect to induce host anti-tumor immunity and may prove to be a useful form of cancer gene therapy.
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Grymula, Kasia, Maciek Tarnowski, Radoslaw Maksym, Magdalena Kucia, Janina Ratajczak, and Mariusz Z. Ratajczak. "An in Vitro and in Vivo Evidence That Human Rhabdomyosarcomas (RMS) Express Functional CXCR7 Receptor: Overlapping and Distinct Role of CXCR4-SDF-1 and CXCR7-SDF-1/ITAC Axes in Regulating Metastatic Behavior of RMS Cells." Blood 112, no. 11 (November 16, 2008): 4732. http://dx.doi.org/10.1182/blood.v112.11.4732.4732.
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Abstract Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma of adolescents and children that frequently infiltrates the bone marrow (BM). We have demonstrated that the a-chemokine stromal-derived factor (SDF)-1-CXCR4 axis (Blood2002;100:2597, Cancer Res. 2003;63:7926, Cancer Res.2007;67:2131) plays an important role in RMS metastases. With the recent description of CXCR7, a new receptor for SDF-1 that also binds the interferon-inducible T cell-alpha chemoattractant (ITAC) chemokine, we become interested in the role of the CXCR7-SDF-1/ITAC axis in RMS metastasis. To address this issue, we evaluated 7 highly metastatic alveolar RMS (ARMS) and 3 less metastatic embryonal RMS (ERMS) cell lines. We found that all RMS cell lines express CXCR7 in contrast to CXCR4, which was expressed by 7 of 10 RMS cell lines only. CXCR4 was expressed at a much higher level by highly metastatic ARMS lines while CXCR7 was expressed at a high level on the less metastatic ERMS lines. More importantly, CXCR7 receptor on RMS cell lines was functional after stimulation with ITAC and SDF-1 as evidenced by MAPKp42/44-, AKT-, and STAT-3 phosphorylation, chemotaxis, cell motility, and adhesion assays. We also noticed that CXCR7 undergoes rapid internalization after stimulation with SDF-1 and ITAC, is a lipid raft-associated receptor, and, surprisingly, has a downregulated expression in response to hypoxia. We also noticed that similarly to CXCR4, signaling from activated CXCR7 was not associated with increased RMS proliferation or cell survival. Thus, we conclude that both CXCR4 and CXCR7 are not affecting proliferation of RMS cells; however they play an important role in both SDF-1- and ITAC-directed metastasis. For the first time, we also identify ITAC as a new regulatory chemokine that is actively involved in this process. In conclusion, since CXCR7 is more important in adhesion and becomes down-regulated during hypoxia, this changes the balance in SDF-1 signaling through both receptors (CXCR7/CXCR4). As a result, SDF-1 activates more robust CXCR4 receptor, which promotes chemotactic responses of RMS cells. As a biological consequence, this switch in SDF-1 receptor signaling increases the metastatic potential of RMS by mobilizing tumor cells to egress from the tumor into the peripheral blood and lymph and migrate to new tissue locations. We also conclude that targeting of the CXCR-SDF-1 axis alone without simultaneous blockage of CXCR7 will be an inefficient strategy to inhibit metastasis of RMS cells. This is currently being tested in our laboratories in immunodeficient mice inoculated with human RMS cells.
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Li, Yi, Yuhuan Zheng, Li Yang, Qiang Wang, Enguang Bi, Tianshu Li, Yong Lu, et al. "Chemokines CCL14 and CCL3 Facilitate Monocytes/Macrophage Infiltration in Multiple Myeloma Bone Marrow." Blood 124, no. 21 (December 6, 2014): 3380. http://dx.doi.org/10.1182/blood.v124.21.3380.3380.
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Abstract Drug resistance is the most common reason for treatment failure in multiple myeloma (MM), a plasma cell cancer of the bone marrow (BM). Our previous studies have shown that macrophage (MΦ) infiltration is increased in MM BM, and these MM-associated MΦs induce MM drug resistance by protecting MM cells from chemotherapeutic-induced cell death. A recently published clinical study also suggests that the number of BM MΦs negatively correlates with MM drug response and patient survival. Why MM BM harbors more MΦ is not well understood. In general, MΦs are derived from circulating monocytes, and monocytes are recruited to tissues by chemokines and differentiate into MΦs. In this study, we examined monocyte/MΦ chemokine expression in MM BM and determined that CCL14 and CCL3 were functional chemokines that regulated monocyte/MΦ infiltration in MM BM. To identify chemokines that regulate monocyte/MΦ infiltration in the MM tumor bed, we examined a panel of chemokines expressed in MM patient BM cells. Specifically, total BM cells (both CD138+ and CD138- cells) from MM patients were assayed by qPCR for target gene expression analysis. MM BM cells highly expressed CCL2 (MCP-1), CCL3 (MIP-1α), CCL4 (MIP-1β), CCL5 (RANTES), and CCL14 (HCC-1), but not CCL8 (MCP-2), CCL7 (MCP-3) or CCL13 (MCP-4). Next, we compared expression of those chemokines in MM BM vs. healthy BM aspirates by ELISA. MIP-1 α and HCC-1 were highly expressed in MM BM aspirates (n=11), but not in BM from healthy donors (n=7; P<0.05). Immunohistochemistry staining also confirmed that MM BM (n=5 patients) highly expressed MIP-1 α and HCC-1. Based on our findings, we hypothesized that elevated MΦ infiltration in MM BM might be due to MM BM overexpression of MIP-1α and HCC-1. To test this hypothesis, we first examined MIP-1α and HCC-1 function in monocyte migration. In vitro chemotactic assay showed that adding MIP-1α or HCC-1 neutralizing antibody inhibited monocyte migration to cocultured BM stromal cells (BMSCs) and MM cells (P<0.05). The antibodies also inhibited monocyte migration to ex vivo cultured BM cells from MM patients (P<0.05). In a murine MM mouse model, C57BL/KawRij mice inoculated with 5TGM1, a murine MM cell line, developed tumors in hind leg bones. Both flow cytometry analysis and immunohistochemistry staining suggested that the tumor-bearing mice had an increased number of MΦs in the BM, compared with healthy mice (P<0.05). Because HCC-1 does not have murine homology but it has the highest amino acid sequence similarity to MIP-1α, we treated the mice with MIP-1α neutralization antibody. Intra-peritoneal injection of mouse MIP-1α antibody decreased the MΦ number in BM (P<0.05). Such in vivo findings strongly suggest that MIP-1α regulates MΦ infiltration in MM BM. We also examined the source cells that contributed to high MIP-1 α and HCC-1 expression in MM BM. Primary MM cells (CD138+) and non-malignant BM cells (CD138-) were isolated from patient (n=5) BM aspirates. qPCR analysis showed that both CD138+ and CD138- cells had high MIP-1α and HCC-1 expression. Further, BMSC/MM coculture stimulated MIP-1α overexpression in BMSCs. Finally, we examined the association between MIP-1α or HCC-1 expression and the number of BM MΦ in MM patients. The chemokine expression in BM aspirates was determined by ELISA, and the number of MΦ was measured by flow cytometry analysis for CD14+/CD68+ cells. We found that MIP-1α expression was positively associated with the number of BM MΦs (P<0.05). To summarize, our findings suggest that CCL14 and CCL3 facilitate monocyte/MΦ infiltration in MM BM. Inhibiting these 2 chemokines may decrease the number of MM-associated MΦs, therefore increasing MM cell vulnerability to chemotherapy. Disclosures No relevant conflicts of interest to declare.
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Steinbach, Daniel, Alexander Schramm, Angelika Eggert, Susann Wittig, Nadine Pfaffendorf, Astrid Voigt, Felix Zintl, and Bernd Gruhn. "Identification of a Set of Seven Genes for the Monitoring of Minimal Residual Disease in Pediatric Acute Myeloid Leukemia." Blood 106, no. 11 (November 16, 2005): 1461. http://dx.doi.org/10.1182/blood.v106.11.1461.1461.
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Abstract A stepwise approach which combined genome wide expression profiling and a TaqMan realtime PCR based screening was used to identify new markers for the monitoring of minimal residual disease (MRD) in acute myeloid leukemia (AML). Leukemic cells from 52 children with AML were analyzed. Seven genes were identified which are vastly over-expressed in many patients with AML compared to healthy bone marrow: CCL23, GAGED2, MSLN, SPAG6, and ST18 as well as the previously described markers WT1 and PRAME. This set of genes was analyzed in 141 follow-up samples from 25 patients. The expression of all genes decreased to normal levels in patients who achieved a continuous complete remission. Elevated levels of MRD markers were found prior to relapse in 7 out of 10 patients who relapsed. This set of genes should allow a sensitive and specific monitoring of MRD in AML. Notably, some of these markers could also serve as therapeutic targets or might be involved in leukemogenesis. MSLN is already used as a target for immunotherapy in clinical trials in other malignancies. GAGED2 and SPAG6 belong to the family of cancer testis genes which are also studied intensively as targets for immunotherapy. ST18 is a recently discovered tumor suppressor which was not yet described in hematological malignancies. CCL23 is a chemokine that inhibits the proliferation of healthy hematological stem cells. Names, symbols, and geneID of seven MRD markers Gene Symbol Gene Name GeneID CCL23 chemokine (C–C motif) ligand 23 6368 GAGED2 G antigen, family D, 2 9503 MSLN Mesothelin 10232 SPAG6 sperm associated antigen 6 9576 ST18 suppression of tumorigenicity 18 9705 WT1 Wilms tumor 1 7490 PRAME preferentially expressed antigen in melanoma 23532
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Tang, Yucheng, Jonathan Maynard, Hakan Akbulut, Phyllis-Jean Linton, and Albert B. Deisseroth. "Vector Prime-Protein Boost Vaccine Induces Immune Response Against “Self-Antigens” Associated with Epithelial Neoplasms and Tumor Vascular Endothelial Cells." Blood 106, no. 11 (November 16, 2005): 5533. http://dx.doi.org/10.1182/blood.v106.11.5533.5533.
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Abstract In order to develop a method to overcome the immune tolerance of cancer, we have designed an Ad-sig-TAA/ecdCD40L adenoviral vector vaccine for the in vivo activation and tumor antigen loading of dendritic cells (DCs). Subcutaneous (sc) injection of the Ad-sig-TAA/ecdCD40L adenoviral vector results in the secretion for 10 days from the vector infected cells of a fusion protein composed of a fragment of a tumor associated antigen (TAA) fused to the extracellular domain (ecd) of the CD40 ligand (CD40L). CD40L is a homo-trimeric protein normally found on B cells and helper CD4+ T cell lymphocytes. All of the sequences necessary to stabilize this trimeric structure of the protein are contained within the ecd of the CD40L protein. The binding of the TAA/ecdCD40L protein to DCs induces migration of these DCs to the regional lymph nodes. These DCs carry fragments of TAA bound to surface MHC Class I molecules. We have shown that the Ad-sig-TAA/ecdCD40L vector strategy can induce a cellular and humoral immune that persists for over a year indicating that a durable memory response is generated. We showed that sc injections of the Ad-sig-rH2N/ecdCD40L vector in rH2N.Tg mice induces a cellular and humoral immune response against the rat Her-2-Neu (rH2N) antigen which is associated with breast cancer. We showed that the sc injection of the Ad-sig-rH2N/ecdCD40L adenoviral vector in a rH2N.Tg transgenic mouse induced resistance to the growth of rH2N positive cancer cells in mice previously anergic to the rH2N antigen. We demonstrated that the sc injection of the Ad-sig-hMUC-1/ecdCD40L vector suppressed the growth of tumor cells positive for the human MUC-1 (hMUC-1) antigen in hMUC-1.Tg mice which were previously anergic to the hMUC-1 antigen. The sc injection of the Ad-sig-hMUC-1/ecdCD40L vector followed by sc injection of two booster injections of the hMUC-1/ecdCD40L protein induced high levels of hMUC-1 specific tumor infiltrating effector CD8 positive T cells and hMUC-1 antibodies which bound to human breast and prostate cancer cells. In addition, we recently showed that the Ad-sig-TAA/ecdCD40L strategy could be used to activate a cellular and humoral immune response against Annexin A1 (AnxA1), which is a marker uniquely displayed on the luminal membrane of tumor vascular endothelial cells but not on the luminal membrane of vascular endothelial cells of normal tissue. The subcutaneous injection of the Ad-sig-AnxA1/ecdCD40L vector suppressed the growth of AnxA1 negative tumor cells in a syngeneic mouse tumor model. This vector prime/protein boost vaccination was found to induce increased levels of effector CD8 positive T cells in the target tumor. These effector T cells were shown express increased levels of the genes encoding the CCR5 chemokine receptor and the CCL3 chemokine ligand which promote the infiltration of antigen specific effector T cells in the target tumor tissues. The response to cancer vaccines is often reduced in older individuals in part due to an intrinsic functional defect in CD4 cells. The Ad-sig-TAA/ecdCD40L vaccine may circumvent this defect because we have shown that the induction of the immune response is CD4 independent. These data suggest that this vector prime-protein boost vaccination strategy will be useful in the reduction of the frequency of recurrence following initial therapy for a wide variety of neoplastic diseases.
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Robson, Neil C., David J. Phillips, Tristan McAlpine, Amanda Shin, Suzanne Svobodova, Tracey Toy, Vinochani Pillay, et al. "Activin-A: a novel dendritic cell–derived cytokine that potently attenuates CD40 ligand–specific cytokine and chemokine production." Blood 111, no. 5 (March 1, 2008): 2733–43. http://dx.doi.org/10.1182/blood-2007-03-080994.
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Activin-A is a transforming growth factor-β (TGF-β) superfamily member that plays a pivotal role in many developmental and reproductive processes. It is also involved in neuroprotection, apoptosis of tumor and some immune cells, wound healing, and cancer. Its role as an immune-regulating protein has not previously been described. Here we demonstrate for the first time that activin-A has potent autocrine effects on the capacity of human dendritic cells (DCs) to stimulate immune responses. Human monocyte-derived DCs (MoDCs) and the CD1c+ and CD123+ peripheral blood DC populations express both activin-A and the type I and II activin receptors. Furthermore, MoDCs and CD1c+ myeloid DCs rapidly secrete high levels of activin-A after exposure to bacteria, specific toll-like receptor (TLR) ligands, or CD40 ligand (CD40L). Blocking autocrine activin-A signaling in DCs using its antagonist, follistatin, enhanced DC cytokine (IL-6, IL-10, IL-12p70, and tumor necrosis factor-α [TNF-α]) and chemokine (IL-8, IP-10, RANTES, and MCP-1) production during CD40L stimulation, but not TLR-4 ligation. Moreover, antagonizing DC-derived activin-A resulted in significantly enhanced expansion of viral antigen-specific effector CD8+ T cells. These findings establish an immune-regulatory role for activin-A in DCs, highlighting the potential of antagonizing activin-A signaling in vivo to enhance vaccine immunogenicity.
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Thiele, Michael, Seamas C. Donnelly, and Robert A. Mitchell. "OxMIF: a druggable isoform of macrophage migration inhibitory factor in cancer and inflammatory diseases." Journal for ImmunoTherapy of Cancer 10, no. 9 (September 2022): e005475. http://dx.doi.org/10.1136/jitc-2022-005475.
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Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine with a pleiotropic spectrum of biological functions implicated in the pathogenesis of cancer and inflammatory diseases. MIF is constitutively present in several cell types and non-lymphoid tissues and is secreted after acute stress or inflammation. MIF triggers the release of proinflammatory cytokines, overrides the anti-inflammatory effects of glucocorticoids, and exerts chemokine function, resulting in increased migration and recruitment of leukocytes into inflamed tissue. Despite this, MIF is a challenging target for therapeutic intervention because of its ubiquitous nature and presence in the circulation and tissue of healthy individuals. Oxidized MIF (oxMIF) is an immunologically distinct disease-related structural isoform found in the plasma and tissues of patients with inflammatory diseases and in solid tumor tissues. MIF converts to oxMIF in an oxidizing, inflammatory environment. This review discusses the biology and activity of MIF and the potential for autoimmune disease and cancer modification by targeting oxMIF. Anti-oxMIF antibodies reduce cancer cell invasion/migration, angiogenesis, proinflammatory cytokine production, and ERK and AKT activation. Anti-oxMIF antibodies also elicit apoptosis and alter immune cell function and/or migration. When co-administered with a glucocorticoid, anti-oxMIF antibodies produced a synergistic response in inflammatory models. Anti-oxMIF antibodies therefore counterregulate biological activities attributed to MIF. oxMIF expression has been observed in inflammatory diseases (eg, sepsis, psoriasis, asthma, inflammatory bowel disease, and systemic lupus erythematosus) and oxMIF has been detected in ovarian, colorectal, lung, and pancreatic cancers. In contrast to MIF, oxMIF is specifically detected in plasma and/or tissues of diseased patients, but not in healthy individuals. Therefore, as a druggable isoform of MIF, oxMIF represents a potential new therapeutic target in inflammatory diseases and cancer. Fully human, monoclonal anti-oxMIF antibodies have been shown to selectively bind oxMIF in preclinical and phase I studies; however, additional clinical assessments are necessary to validate their use as either a monotherapy or in combination with standard-of-care regimens (ie, immunomodulatory agents/checkpoint inhibitors, anti-angiogenic drugs, chemotherapeutics, and glucocorticoids).
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Ware, Michael, Bhavana Pavuluri, Aubrey Smith, Megan Wyatt, Guillermo Rangel RIvera, Anna Cole, and Chrystal Paulos. "9 BRAF mutations are associated with T-helper cell infiltration and polarization in melanoma." Journal for ImmunoTherapy of Cancer 9, Suppl 2 (November 2021): A9. http://dx.doi.org/10.1136/jitc-2021-sitc2021.009.
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BackgroundBRAF mutations are highly prevalent in patients with melanoma (50–65%), and mark tumors which are responsive to combination immune checkpoint inhibition (ICI) with nivolumab (αPD-1) and ipilimumab (αCTLA-4). Interestingly, this combination does not improve outcomes over nivolumab alone for patients with BRAF wild-type melanoma.1 We propose that BRAF mutations shape the immunological response to ICI through tumor derived cytokines and chemokines. While BRAF mutations can influence cytokine production and myeloid cell infiltration, the influence of BRAF mutations on tumor infiltrating CD4+ T-helper cells is underexplored in all tumor types. However, one study described a unique association between BRAF mutant melanoma and signatures of Th17 biology using transcriptomic analysis.2 We hypothesize that BRAF mutations create a unique cytokine and chemokine milieu which support the infiltration and polarization of Th17 cells.MethodsTo address this hypothesis we employed the congenic BRAF wild-type murine melanoma lines B16F10 and YUMM4.1, and the BRAF mutant line YUMM1.7. These cell lines were implanted subcutaneously into female C57BL/6 mice. Blood cytokines, splenocytes and tumor infiltrating lymphocytes were analyzed at 1 week and 3 weeks post tumor implantation to simulate both early stage and late-stage tumors respectively. Flow cytometry was used to define T-helper cell and myeloid cell phenotypes. In vitro analysis of chemokines and cytokines produced by each cell line were conducted via array and confirmed by ELISA.ResultsTh1 and Th17 cells preferentially infiltrated early stage (1 week) BRAF wild-type and mutant tumors respectively while the CD4+ compartment of all tumors was dominated by an overwhelming Treg presence. The CD4+ compartment of endpoint (3 week) B16F10 tumors were almost entirely dominated by Tregs, while YUMM1.7 tumors were infiltrated by a diverse array of T-helper cells. In parallel with these results, we found YUMM1.7 tumors contained more dendritic cells and F4/80hiMHC-II+ macrophages as a percentage of the CD45+ infiltrate. Unique chemokine profiles were associated with each cell line, highlighted by relatively high expression of CXCL10 by BRAF wild-type lines and CXCL12 by both YUMM4.1 and YUMM1.7 cell lines.ConclusionsThis work indicates the mutational landscape of melanoma can dynamically impact CD4+ T cell responses to melanoma. This ongoing work is directly translatable and will aid the development of novel cellular therapies tailored to specific immunological phenotypes of patients. Further, this work may help explain disparities in the response to ICI observed between patient populations with defining mutational signatures.AcknowledgementsWe would like to acknowledge Emory University, The Winship Shared Resource, and the Pediatrics/Winship Flow Cytometry CoreReferencesMa VT, Daignault-Newton S, Waninger JJ, Journey S, Chopra Z, Tezel A, Redman BG, Fecher LA, Green MD, Alva AS, Lao CD. The impact of BRAF mutation status on clinical outcomes with anti-PD-1 monotherapy versus combination ipilimumab/nivolumab in treatment-naïve advanced stage melanoma. Pigment Cell Melanoma Res. 2021 May;34(3):629–640.Tomei S, Bedognetti D, De Giorgi V, Sommariva M, Civini S, Reinboth J, Al Hashmi M, Ascierto ML, Liu Q, Ayotte BD, Worschech A, Uccellini L, Ascierto PA, Stroncek D, Palmieri G, Chouchane L, Wang E, Marincola FM. The immune-related role of BRAF in melanoma. . 2015Mol OncolJan;9(1):93–104.Ethics ApprovalAll animal studies were conducted under the approval of the Emory Institutional Animal Care and Use Committee and ethical guidelines established by this committee were strictly adhered to.
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Johnson, Kelly Elizabeth, Kellie R. Machlus, Saleh El-Husayni, Rajesh Kulenthirarajan, Jodi A. Forward, Joseph E. Italiano, and Elisabeth M. Battinelli. "Platelets Promote Breast Cancer Metastasis By Reprogramming Tumor Cells to Produce IL-8." Blood 126, no. 23 (December 3, 2015): 2233. http://dx.doi.org/10.1182/blood.v126.23.2233.2233.
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Abstract Platelets, primarily known for their role in hemostasis, are now recognized to play an integral role in cancer progression and metastasis. Recent evidence has established that platelets are activated by contact with breast tumor cells, leading to the release of hundreds of growth factors, cytokines, chemokines and angiogenesis mediators that could influence tumor growth and metastasis. Indeed, work from our group has demonstrated that factors released from activated platelets promote both metastasis and angiogenesis. However, little is known about the specific factors and signaling pathways that mediate this critical platelet-tumor cell cross-talk. To address this question, we performed an angiogenesis array (Ray Biotech) to identify specific pro-angiogenic and pro-metastatic factors released by tumor cells during platelet-tumor cell interactions. We identified several factors that were secreted by MCF-7 breast tumor cells in response to activated platelet releasate, including high levels of interleukin 8 (IL-8, CXCL8). IL-8 is a cytokine known to play a critical role in metastasis and angiogenesis and is elevated in the serum and tumor tissue of breast cancer patients. We confirmed that exposure to platelets strongly induced the production of IL-8 in several human breast cancer cell lines (MDA-MB-231, BT-20, SKBR-3 and MCF-7) by ELISA and found that platelets themselves do not contain detectable levels of IL-8. Furthermore, IL-8 production was highest in the more aggressive, triple negative MDA-MB-231 and BT-20 lines, suggesting a link between platelet-induced IL-8 and tumor subtype. To identify the specific component or components of platelet releasate responsible for driving tumor cell IL-8, we first characterized the contents of activated platelet releasate by array (Ray Biotech) and found an abundance of both chemokine (C-C motif) ligand 5 (CCL5, RANTES) and epidermal growth factor (EGF). Next, we treated breast tumor cell lines directly with recombinant CCL5 or EGF and observed an increase in IL-8 production, however sensitivity to CCL5, EGF or the combination varied among the cell lines tested and may depend on receptor expression. To determine if platelet-derived CCL5 or EGF drives tumor cell IL-8, breast tumor cells were pretreated with the CCL5 receptor (CCR5) blocker maraviroc or the EGFR blocker AG-1478 and then exposed to platelets. Blocking CCR5 abrogated the induction of IL-8 in response to platelets in the cell lines that were sensitive to CCL5 while EGFR inhibition diminished induction of IL-8 in response to platelets in the cell lines that were sensitive to EGF. Next we sought to determine the role of platelet-induced IL-8 in metastasis. We performed standard invasion assays using MDA-MB-231 cells transfected with IL-8shRNA or control cells. Platelets were able to increase the invasion of control MDA-MD-231 cells by 5 fold, while IL-8 knockdown reduced the effect of platelets on invasion by 50%. Furthermore, ability of platelets to promote tumor cell migration across an endothelialized membrane was reduced 87% in IL-8 knockdown MDA-MB-231s compared to controls in standard transendothelial migration assays. These results suggest that platelets promote metastasis, in part, by driving tumor cell IL-8. Studies are currently underway to further elucidate the mechanism by which platelets reprogram tumor cells to produce IL-8 and to confirm these findings in vivo. Taken together, these results suggest that platelets, through release of soluble factors, drive tumor cells to produce IL-8 and that blocking this communication can disrupt the pro-metastatic potential of platelets. Ultimately, these studies support targeting specific platelet-tumor cell interaction as a novel means of limiting disease progression in breast cancer. Disclosures No relevant conflicts of interest to declare.
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Flick, Matthew J., Cheryl Rewerts, Carolina Cruz, Joseph S. Palumbo, James P. Luyendyk, Yi Yang, and Stephen F. Konieczny. "Tumor Cell Thrombin/PAR-1 Signaling Drives Pancreatic Ductal Adenocarcinoma Growth and Dissemination." Blood 126, no. 23 (December 3, 2015): 1070. http://dx.doi.org/10.1182/blood.v126.23.1070.1070.
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Abstract Pancreatic ductal adenocarcinoma (PDAC) accounts for ~85% of diagnosed pancreatic cancers and is among the most lethal malignancies. The 5-year survival rate for pancreatic cancer patients has improved only marginally in the last 40 years (3% → 7%), with effectively no change in survival profile for patients with metastatic disease (2%). High mortality is linked to the aggressive and invasive nature of the malignancy and poor efficacy of limited treatment options, which collectively highlight the need for novel treatment strategies. Notably, analyses of pancreatic cancer in patients and animal models have demonstrated that PDAC is associated with robust coagulation system activity. Previous work has shown that patient PDAC tumor cells often express high levels of tissue factor (TF) and protease-activated receptor (PAR)-1. To determine the potential contribution of tumor cell derived-TF and PAR-1 to PDAC growth and metastasis, a novel tumor cell line (termed KPC2) was derived from mice in which PDAC tumorigenesis was induced by activation of two established pancreatic cancer alleles, KrasG12D and Trp53R172H. In transplant studies, tumor growth and experimental metastasis were evaluated using KPC2 cells in which TF or PAR-1 expression was suppressed by shRNA knockdown. In addition, the interplay of tumor-derived TF and PAR-1 with host factors in promoting tumor growth and experimental metastasis were evaluated in mice with genetically imposed deficits in coagulation system components. TF knockdown (to ~10% of the parental line) in KPC2 cells resulted in a significant diminution of both primary tumor growth and experimental metastasis. This reduction appeared to be linked to thrombin activity as primary tumor growth and experimental metastasis of parental KPC2 cells were significantly reduced in fIIlow mice (which constitutively express 10% of normal prothrombin) relative to wild-type mice. PAR-1 knockout mice displayed similar KPC2 growth and experimental metastasis to wild-type animals indicating that stromal cell-derived PAR-1 was not significant determinant. In stark contrast, shRNA-mediated knockdown of PAR-1 in KPC2 (to ~10% of the parental line) cells resulted in significantly diminished tumor growth and experimental metastasis. Diminished tumor growth was linked to reduced expression of the macrophage chemokine MCP-1 and the metalloproteinase MMP9 by the tumor cells as well as reduced thrombin-stimulated ERK phosphorylation. Our results suggest that a major mechanism of PDAC growth and dissemination is through TF/thrombin-driven PAR-1 signaling on tumor cells. Disclosures No relevant conflicts of interest to declare.