Academic literature on the topic 'Chemokine biology; cancer biology; tumour immunology'
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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.
Dissertations / Theses on the topic "Chemokine biology; cancer biology; tumour immunology"
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Jiménez, Sánchez Alejandro. "Characterisation of the tumour microenvironment in ovarian cancer." Thesis, University of Cambridge, 2019. https://www.repository.cam.ac.uk/handle/1810/287935.
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The tumour microenvironment comprises the non-cancerous cells present in the tumour mass (fibroblasts, endothelial, and immune cells), as well as signalling molecules and extracellular matrix. Tumour growth, invasion, metastasis, and response to therapy are influenced by the tumour microenvironment. Therefore, characterising the cellular and molecular components of the tumour microenvironment, and understanding how they influence tumour progression, represent a crucial aim for the success of cancer therapies. High-grade serous ovarian cancer provides an excellent opportunity to systematically study the tumour microenvironment due to its clinical presentation of advanced disseminated disease and debulking surgery being standard of care. This thesis first presents a case report of a long-term survivor (>10 years) of metastatic high-grade serous ovarian cancer who exhibited concomitant regression/progression of the metastatic lesions (5 samples). We found that progressing metastases were characterized by immune cell exclusion, whereas regressing metastases were infiltrated by CD8+ and CD4+ T cells. Through a T cell - neoepitope challenge assay we demonstrated that pre- dicted neoepitopes were recognised by the CD8+ T cells obtained from blood drawn from the patient, suggesting that regressing tumours were subjected to immune attack. Immune excluded tumours presented a higher expression of immunosuppressive Wnt signalling, while infiltrated tumours showed a higher expression of the T cell chemoattractant CXCL9 and evidence of immunoediting. These findings suggest that multiple distinct tumour immune microenvironments can co-exist within a single individual and may explain in part the hetero- geneous fates of metastatic lesions often observed in the clinic post-therapy. Second, this thesis explores the prevalence of intra-patient tumour microenvironment het- erogeneity in high-grade serous ovarian cancer at diagnosis (38 samples from 8 patients), as well as the effect of chemotherapy on the tumour microenvironment (80 paired samples from 40 patients). Whole transcriptome analysis and image-based quantification of T cells from treatment-naive tumours revealed highly prevalent variability in immune signalling and distinct immune microenvironments co-existing within the same individuals at diagnosis. ConsensusTME, a method that generates consensus immune and stromal cell gene signatures by intersecting state-of-the-art deconvolution methods that predict immune cell populations using bulk RNA data was developed. ConsensusTME improved accuracy and sensitivity of T cell and leukocyte deconvolutions in ovarian cancer samples. As previously observed in the case report, Wnt signalling expression positively correlated with immune cell exclusion. To evaluate the effect of chemotherapy on the tumour microenvironment, we compared site-matched and site-unmatched tumours before and after neoadjuvant chemotherapy. Site- matched samples showed increased cytotoxic immune activation and oligoclonal expansion of T cells after chemotherapy, unlike site-unmatched samples where heterogeneity could not be accounted for. In addition, low levels of immune activation pre-chemotherapy were found to be correlated with immune activation upon chemotherapy treatment. These results cor- roborate that the tumour-immune interface in advanced high-grade serous ovarian cancer is intrinsically heterogeneous, and that chemotherapy induces an immunogenic effect mediated by cytotoxic cells. Finally, the different deconvolution methods were benchmarked along with ConsensusTME in a pan-cancer setting by comparing deconvolution scores to DNA-based purity scores, leukocyte methylation data, and tumour infiltrating lymphocyte counts from image analysis. In so far as it has been benchmarked, unlike the other methods, ConsensusTME performs consistently among the top three methods across cancer-related benchmarks. Additionally, ConsensusTME provides a dynamic and evolvable framework that can integrate newer de- convolution tools and benchmark their performance against itself, thus generating an ever updated version. Overall, this thesis presents a systematic characterisation of the tumour microenvironment of high grade serous ovarian cancer in treatment-naive and chemotherapy treated samples, and puts forward the development of an integrative computational method for the systematic analysis of the tumour microenvironment of different tumour types using bulk RNA data.
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De, Silva Jasenthu L. P. "The role of the transcription factor FOXP1 in the immune response to breast cancer." Doctoral thesis, Universite Libre de Bruxelles, 2018. https://dipot.ulb.ac.be/dspace/bitstream/2013/264152/4/Thesis.pdf.
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Breast cancer (BC) was not initially considered an immunogenic tumor; however, recent data show that immune-related factors are associated with patient prognosis and the response to treatment. Several large adjuvant clinical trials have shown that tumor infiltrating lymphocytes (TIL) are significantly associated with a better prognosis and can also predict responsiveness to pre-operative chemotherapy, particularly in the triple negative (TN) & HER2+ BC subtypes (Carsten Denkert et al. 2010; Loi et al. 2013a). Recently, the presence of ectopic lymph node-like structures characterized by distinct T and B cell zones, called tertiary lymphoid structures (TLS), were identified adjacent to the tumor (Gu-Trantien et al. 2013) in 60% of BC (Buisseret et al. 2017b) and linked with a good prognosis (Gu-Trantien et al. 2013). The mechanisms involved in TLS formation and activities and their impact on tumor immunity is relatively unknown. TIL infiltration and TLS formation are likely regulated, in part, by transcription factors (TF) that control cytokine/chemokine production within the tumor microenvironment (TME) (Pimenta and Barnes, 2014). One such TF, the forkhead box protein 1 (FOXP1) is abnormally expressed in various human tumors and has a known role in regulating immune cell functions. Contradictory data on FOXP1 expression together with a lack of information on its immune regulation led us to explore its role in this tumor type. The first part of this thesis research focused on FOXP1-mediated regulation in BC. Gene/protein analysis was examined in the four BC molecular subtypes, revealing its enriched expression in estrogen receptor positive (ER+) tumors (Luminal A/B). Luminal BC is generally less infiltrated compared with frequently high TIL infiltration in ER negative (ER-) tumors (i.e. HER2+ and TN) [reviewed in (Solinas et al. 2017a) and (Loi et al. 2014)]. We found that high FOXP1 expression in a cohort of untreated primary BC was significantly associated with a lower TIL and fewer TLS compared to FOXP1 low (FOXP1lo) tumors. This observation led us to investigate the effect of FOXP1 on cytokines and chemokines potentially involved in TIL recruitment and/or TLS formation. BC cancer cell lines were used to silence [MCF7; FOXP1hi] or overexpress [MDA-MB-231; FOXP1lo] FOXP1 expression. FOXP1 repression upregulated a number of cytokines and chemokines involved in T and B cell migration and function, while FOXP1 overexpression repressed a majority of the same factors. Expression analysis of the major T and B cell cytokine and chemokine genes was performed for FOXP1lo and FOXP1hi primary BC. These data reveal that FOXP1hi BCs have significant decreases in CXCL9, CXCL10, CXCL11, CXCL13, CX3CL1, CCL20, IL2, IL21, granzyme B and IFNγ and high levels of the immunosuppressive cytokines, IL10 and TGFβ. We next performed a lymphocyte migration assay using primary tumor supernatants prepared from FOXP1lo and FOXP1hi BC finding significantly decreased migration of total CD45+ lymphocytes, B cells, helper (CD4+) and cytotoxic (CD8+) T cells using FOXP1hi compared to FOXP1lo SN. Overall, our data suggest that FOXP1 plays an important role in repressing anti-tumor immune responses by negatively regulating TIL migration directed by specific cytokines and chemokines.The second part of this thesis research focused on the role FOXP1 plays in BC TLS. FOXP1 expression in T and B cell TIL and TLS was evaluated using RT-qPCR, multicolor flow cytometry, immunofluorescence (IF) and immunohistochemistry (IHC) and fresh, fixed and frozen breast tissues. Based on the FOXP1 expression two types of TLS were identified in BC: 1) TLS containing a germinal center (GC-TLS) and 2) TLS lacking a GC (non-GC-TLS). Examination of proteins specifically associated with active humoral immune responses allowed us to identify GC-TLS but not non-GC-TLS as functional. Gene expression analysis of micro-dissected tissues revealed distinct immune profiles that characterize B cell follicles in tonsils and spleen as well as aggregates, non-GC-TLS and GC-TLS in BC. This analysis further demonstrates that ongoing cell-mediated immune responses are associated with GC-TLS. The findings from this thesis research add important information to our understanding of how immune responses are initiated and maintained in BC and provide further insight into the identification and organization of functional immune responses at the tumor site.Doctorat en Sciences biomédicales et pharmaceutiques (Médecine)
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Hamer, Rebecca K. "The structural basis of immune receptor signalling." Thesis, University of Oxford, 2008. http://ora.ox.ac.uk/objects/uuid:32312040-2e22-4fe3-b05e-6f868233e27e.
Full textAbstract:
This work investigates the mechanisms of binding of T cell receptors (TCRs) to Class I MHC-peptide complexes (pMHC). The structure of a TCR specific for the Melan-A tumour antigen bound to its cognate pMHC was solved to a resolution of 2.5 Å which gives insight into how this TCR could be mutated to optimize binding and subsequently used as a cancer vaccine. Detailed sequence and geometric analyses of all currently available structures of Class I TCR-pMHC complexes revealed that TCRs can bind to pMHC with a range of orientations, yet always focus on the central portion of the peptide and use a specific subset of six residues on the MHC helices for binding. The most striking finding was the use of aromatic residues in the TCR CDR loops to bind to residue Q155 on the MHC α2 helix. Attempts were also made to express and purify Toll-like receptors (TLRs) with the aim of solving one or more of these structures. However, despite testing of over 50 different constructs from 12 different TLRs or associated proteins, insufficient soluble protein expression was obtained for crystallization trials. Finally, a protein disorder prediction tool was developed to aid construct design for structural biology studies and improve the chances of obtaining protein crystals. This tool is based on a novel type of neural network and blind tests comparing it to 8 other disorder prediction tools showed it is one of the best in the field. It is freely available at www.strubi.ox.ac.uk/RONN. Analysis of large datasets revealed that the position of order/disorder transitions is quite precisely defined in amino-acid sequences and that transition regions have an amino acid composition distinct from that of bulk ordered and disordered sequences. There is a steady decrease in order-promoting residues on the ordered side of boundaries as well as a weak sequence signal, both of which signify the approaching disorder and may prove useful for improving existing disorder prediction tools.
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Balathasan, Lukxmi. "Characterising the role of circulating immune cells in brain metastasis." Thesis, University of Oxford, 2012. http://ora.ox.ac.uk/objects/uuid:e7620d30-7e4a-468b-b819-db4cf27eaef6.
Full textAbstract:
Brain metastasis is a frequent occurrence in cancer patients and carries a high mortality rate. The incidence of brain metastasis is on the rise, highlighting the need for improved therapeutic intervention. Immune cells have been shown to promote disseminated tumour cells to colonise the lung and liver. Therefore, we aim to determine whether immune cells also facilitate brain metastasis by describing the host immune response to tumour cells attached to the brain vasculature. We developed a model of brain metastasis by using ultrasound guidance to perform intracardiac injection of tumour cells. Using this method, we identified highly and weakly brain metastatic cell lines. To understand how cancer cells develop into brain metastases, we analysed brains harvested 4 h- 14 d after tumour injections. At 4 h after intracardiac injection, only cell lines that developed into brain metastases were found adhered to the brain vasculature in high numbers. A small number of arrested tumour cells clustered with CD45⁺ immune cells. These tumour-CD45 clusters persisted over time whilst the frequency of solitary tumour cells declined. Tumour-associated CD45⁺ immune cells were identified to be Ly6G⁺Gr-1⁺CD11c⁻ myeloid cells. Considerably more tumour-CD45⁺ immune cell clusters were found within the brain vasculature when tumour cells were injected into mice bearing a primary tumour. Increased tumour-CD45⁺ immune cells clusters correlated with an increased number of brain metastases in the same group of mice. We also found a positive association between increased tumour-immune clusters and levels of tumour and host derived G-CSF. To establish a causal relationship between tumour cell-CD45 clusters and metastases, we developed an experimental setup for transcranial imaging. Our results suggest that tumour recruited immune cells may promote tumour cell colonisation of the brain and provides a framework for further investigation.
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Jain, Jayati. "Engineering antibodies to study and improve immunomagnetic isolation of tumour cells." Thesis, University of Oxford, 2013. http://ora.ox.ac.uk/objects/uuid:81355801-b331-4705-bfef-204a29ee0347.
Full textAbstract:
Cell separation based on antibody-targeted magnetic beads has been widely used in a number of applications in immunology, microbiology, oncology and more recently, in the isolation of circulating tumour cells (CTCs) in cancer patients. Although other cell separation techniques such as size based cell filtration and Fluorescence Activated Cell Sorting have also been in popular use, immunomagnetic cell isolation possesses the advantages of high throughput, good specificity and reduced cell stress. However, certain fundamental features of the cell-bead interface are still unknown. In this study, some of the key features of the cell-bead synapse were investigated in an effort to improve the efficiency of immunomagnetic cell isolation and reduce its dependence on high expressing cell surface markers. A clinically relevant antibody fragment (Fab) against tyrosine kinase receptor HER2 was applied to study the immunomagnetic isolation of HER2 expressing cancer cells. First, the minimum number of target proteins required on a cell for it to be isolated was determined. Second, the importance of the primary antibody affinity was investigated, using a series of Fab mutants with known kinetics and it was shown that despite starting with sub-nanomolar affinity, improving Fab affinity increased cell isolation. Third, the influence of the connection between the primary antibody and the bead was studied by comparing Fab bridged to the magnetic bead via a secondary antibody, Protein L or streptavidin; the high affinity biotin-streptavidin linkage increased isolation sensitivity by an order of magnitude. Fourth, the effect of manipulating cytoskeletal polymerization and cell membrane fluidity using small molecules was tested; cholesterol depletion decreased isolation and cholesterol loading increased cell isolation. The insights from these observations were then applied to isolate a panel of cell lines expressing a wide range of surface HER2. While the standard approach isolated less than 10% of low HER2 expressing cancer cells from spiked rabbit and human blood, our enhanced approach with the optimized cholesterol level, antibody affinity and antibody-bead linkage could specifically isolate more than 80% of such cells. The final part of this work focussed on developing an antibody clamp that could physically restrict the antigen within its binding site on the Fab and prevent antigen dissociation, using the HER2-Fab complex and the anti-myc peptide antibody 9E10. Work from this thesis provides useful insights into the molecular and cellular parameters guiding immunomagnetic cell isolation and can be used to extend the range of target receptors and biomarkers for tumour cell isolation and other types of cell separation, thereby enhancing the power and capacity of this approach.
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Harata-Lee, Yuka. "The role of the atypical chemokine receptor CCX-CKR in progression and metastasis of cancer." Thesis, 2012. http://hdl.handle.net/2440/80399.
Full textAbstract:
The significance of chemokine receptors CCR7, CCR9 and their ligands CCL19, CCL21, and CCL25 in various types of cancer including mammary carcinoma and melanoma has been highlighted over the last decade. The atypical chemokine receptor CCK-CKR is a high affinity receptor for these chemokine ligands but rather than inducing classical downstream signalling events promoting migration, it instead sequesters and targets its ligands for degradation. Therefore, CCX-CKR has been proposed to regulate chemokine bioavailability in vivo. This putative function of CCX-CKR to regulate the levels of pro-tumourigenic chemokines initially led to the hypothesis that local and systemic regulation of chemokine levels by CCX-CKR influences tumour growth and metastasis in vivo, and ultimately, targeting of CCX-CKR could be an effective cancer therapy. Three broad approaches were taken to investigate the role of CCX-CKR in tumour progression and metastasis including overexpression of the receptor on tumour cells, deletion from the mouse host and receptor expression knockdown in tumour cells. The results revealed that overexpression of CCX-CKR on 4T1.2 mouse mammary carcinoma cells inhibits orthotopic tumour growth. However, this effect could not be correlated with chemokine scavenging in vivo and was not attributed to host adaptive immunity from experiments performed during the course of the current study. On the other hand, overexpression of CCX-CKR on 4T1.2 cells also resulted in enhanced spontaneous metastasis and haematogenous metastasis in vivo. In vitro characterisation of tumourigenicity of 4T1.2 cells revealed that overexpression of CCX-CKR rendered them more invasive, less adherent to the ECM and to each other and more resistant to anoikis. These are established characteristics of cells which have undergone EMT and indeed, CCX-CKR overexpressing cells showed a typical expression pattern of EMT markers. In contrast, when endogenous expression of CCX-CKR is deleted in the mouse host, growth and metastasis of E0771 mammary carcinoma and B16 melanoma are inhibited, which is accompanied by elevated levels of CCX-CKR ligands in tumours and relevant naïve tissues from CCX-CKR-deleted mice. Similarly, shRNA-mediated knockdown of endogenous CCX-CKR from B16 melanoma cells leads to the rejection of primary and secondary tumours. This effect is attributed to elevated levels of CCX-CKR ligands and CCR7⁺ and CCR9⁺ leukocytes in tumour tissues, which resulted in an overall enhancement of the host anti-tumour immune response. Consistent with these observations, growth of CCX-CKR knockdown tumours was comparable to that of control tumours in CCR7-deleted mice indicating host CCR7 dependency of CCX-CKR-mediated rejection of B16 melanoma. Together, findings from this study revealed important insights into the complex role of CCX-CKR in cancer progression and highlights CCX-CKR as a novel target for the development of more effective anti-melanoma therapies and potentially for the treatment of other types of cancer which affect millions of people worldwide.Thesis (Ph.D.) -- University of Adelaide, School of Molecular and Biomedical Science, 2012
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Hahn, Sara. "The influence of host immunity on outcomes following hormone therapy for cancer." Thesis, 2008. http://hdl.handle.net/1828/902.
Full textAbstract:
BACKGROUND: We have recently shown that standard treatments for prostate cancer,
specifically hormone therapy (HT) and radiation therapy, induce antigen-specific immune responses in human patients. However, the contribution of these antigen-specific
immune responses to clinical outcomes is not known.
HYPOTHESIS: HT induces tumour-specific antibody and T cell responses that delay or
prevent tumour recurrence.
METHODS: We utilized the androgen-dependent Shionogi tumour cell line. Male DD/S mice bearing established Shionogi tumours (~64 mm2) were castrated to induce tumour regression, similar to HT in human prostate cancer patients. Control mice were not castrated. Mice were monitored for tumour recurrence. Tumour-specific antibody
responses were measured by immunoblot, and T cell responses by ELISPOT and immunohistochemistry. Tumour-specific antigens were identified by serological
screening of a cDNA expression library (SEREX).
RESULTS: Following castration, 32/33 mice experienced complete tumour regression,
while the remaining mouse experienced partial tumour regression. Of the 32 mice that
underwent complete regression, 72% (23/32) experienced tumour recurrence 3-70 days
post-castration, while the remaining 28% (9/32) remained tumour-free for the duration of the experiment until they were sacrificed for analysis (64-86 days post-castration).
Shionogi tumours became heavily infiltrated by CD3+ T cells between 7-14 days post-castration, after which T cell infiltrates became progressively more sparse. Castration induced antibody responses to one or more tumour proteins in approximately one third of mice with an average latency of 21 days. The most common antibody response was
against poly(A) binding protein, nuclear 1 (PABPN1). Interestingly, 71% (17/24) of
mice with recurrent tumours had an antibody response against PABPN1, whereas only 11% (1/9) of mice that remained tumour-free had a PABPN1-specific antibody response. Put another way, the mean tumour-free interval for those mice that had a PABPN1 antibody response was approximately 25 days compared to approximately 63 days for those mice that did not have a PABPN1 antibody response. However, we found a moderate correlation between the timing of the PABPN1-specific antibody response and growth rate of the recurrent tumour, such that if a mouse had a PABPN1-specific antibody response that occurred shortly after castration, it was more likely to have a slower growing recurrent tumour. IFN-γ ELISPOT assays revealed that castration also induced a PABPN1-specific T cell response that persisted for the duration of the
experiment (up to 92 days post-castration). Unexpectedly, this T cell response was
exceedingly stronger in recurrent mice versus non-recurrent mice and was accompanied
by splenomegaly in recurrent mice. Anti-CD3 staining of the recurrent tumours showed
that the CD3+ T cells were confined to the periphery and stroma of the tumours.
CONCLUSIONS: In the androgen-dependent murine Shionogi carcinoma model, HT induces robust antibody and T cell responses to PABPN1 that are associated with unfavourable outcomes. To determine why those mice that do not have PABPN1-specific antibody and T cell responses have better outcomes, we will further delineate the T cell response with respect to CD4+ versus CD8+ subpopulations. Additionally, we will investigate the use of immunomodulatory agents to amplify host CD8+ T cell responses and thereby improve the therapeutic effects of HT.
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(8771426), Saeed Salehin Akhand. "PHARMACOLOGICAL TARGETING OF FGFR SIGNALING TO INHIBIT BREAST CANCER RECURRENCE AND METASTASIS." Thesis, 2020.
Find full textAbstract:
Breast cancer (BC) is one of the deadliest forms of cancers with high incidence and mortality rates, especially in women. Encouragingly, targeted therapies have improved the overallsurvival and quality of life in patients with various subtypes of BC. Unfortunately, these first-line therapies often fail due to inherent as well as acquired resistance of cancer cells. Treatment evading cancer cells can exhibit systemic dormancy in patients over a long period of time without manifesting any symptoms. In a suitable environment, these undetected disseminated tumor cells can relapse in the form of metastasis. Therefore, it is essential to understand the mechanisms of
BC recurrence and to develop durable therapeutic interventions to improve patient’s survival. In this dissertation work, we studied fibroblast growth factor receptors (FGFR), as therapeutic targets to treat the recurrence of drug-resistant and immune-dormant BC metastasis.
The HER2 subtype of BC is characterized by the overexpression of human epidermal growth factor receptor 2 (HER2), which drives elevated downstream signaling promoting tumorigenesis. Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate in which an anti-HER2 antibody targets HER2 overexpressing tumor cells and delivers a highly potent microtubule inhibitor. Using novel models of minimal residual disease (MRD) following T-DM1 treatments, we found that epithelial to mesenchymal transition is a critical process for cells to persist the TDM1 treatments. The upregulation of FGFR1 may facilitate insensitivity to T-DM1. Our data also showed that FGFR1 overexpression in HER2+ tumors leads to a higher incidence of recurrence, and these recurrent tumors show sensitivity towards covalent inhibition of FGFR.
In addition to drug-induced MRD in the primary tumor sites, disseminated tumor cells (DTCs) can demonstrate dormant phenotype via maintaining an equilibrium with immunemediated tumor clearance. Factors affecting such equilibrium may contribute to the recurrence of breast cancers metastasis. We show that such immune-mediated dormancy can be modeled with the 4T07 tumors. These tumors display immune-exclusion phenotypes in metastatic pulmonary organs. The inhibition of FGFR modulates the immune cell compositions of pulmonary organs favoring anti-tumor immunity. However, inhibition of FGFR may also affect T cell receptor downstream signaling, resulting in the inhibition of cytolytic T cell’s function. Finally, we report that combination therapy using the FGFR kinase inhibitor and an immune checkpoint blockade showed effective targeting of metastatic 4T07 tumors.
FGFR signaling as a therapeutic target in various tumors has been an active focus of cancer research. In this dissertation work, we have expanded our understanding of the role of FGFR in the recurrence of drug-resistant breast cancers as well as in the maintenance of an immune evasive microenvironment promoting pulmonary growth of tumors. Moreover, we presented evidence that it is possible to repurpose FGFR targeted therapy alone or in combination with checkpoint blockades to target recurrent metastatic BCs. In the future, our novel models of minimal residual diseases and systemic immune dormancy may act as valuable biological tools to expand our understanding of the minimal residual disease and dormant tumor cells.
Book chapters on the topic "Chemokine biology; cancer biology; tumour immunology"
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Waldmann, Herman. "Cancer immunology." In Oxford Textbook of Cancer Biology, edited by Francesco Pezzella, Mahvash Tavassoli, and David J. Kerr, 330–43. Oxford University Press, 2019. http://dx.doi.org/10.1093/med/9780198779452.003.0023.
Full textAbstract:
Until recently, the prospects for harnessing immune mechanisms to fight cancer were not encouraging. The advent of monoclonal antibodies, both as diagnostics and as probes for molecular function, have been important, while the identification of dendritic cells as a major intermediary between the antigen source and T-cell activation has been crucial. Major advances in molecular biology and the creation of mutant mice lacking defined gene products have pinpointed key molecules influencing immune function. Finally, many translational efforts in vaccination, autoimmune disease, and transplantation have enabled identification of hitherto undervalued mechanisms that the immune system uses to regulate itself. A fuller understanding of self-tolerance mechanisms, tumour antigens, and the tumour microenvironment has catalysed a wide range of novel therapeutic strategies and has also allowed a re-evaluation of mechanisms underlying the benefits of past chemotherapies.
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"Cancer biology." In Oxford Handbook of Cancer Nursing, edited by Mike Tadman and Dave Roberts, 35–50. Oxford University Press, 2007. http://dx.doi.org/10.1093/med/9780198569244.003.0003.
Full textAbstract:
Introduction 36 Differences between normal cells and cancer cells 38 Oncogenes and tumour suppressor genes (TSGs) 40 Tumour growth 42 Metastasis (spread of secondary tumour) 44 Immunology 46 Tumour classification 48 Knowledge of cancer biology has leapt forward in the last 20 years. This has improved understanding of the disease process of cancer and has opened up the opportunity for targeted treatments and methods of screening....
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"Cancer biology." In Oxford Handbook of Cancer Nursing, edited by Mike Tadman, Dave Roberts, Mark Foulkes, Mike Tadman, Dave Roberts, and Mark Foulkes, 31–42. Oxford University Press, 2019. http://dx.doi.org/10.1093/med/9780198701101.003.0003.
Full textAbstract:
This chapter covers a basic understanding of cancer biology, including the role of oncogenes and tumour suppressor genes and their role in controlling the cell cycle. Relevant links are made throughout to applying this knowledge to recent advances in cancer treatment, including immunology and targeted therapies. It also explores metastases and the complex mechanisms involved which enable cancer cells to spread throughout the body. Finally it looks briefly at tumour classification.
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Monnot, Gwennaëlle C., and Pedro Romero. "Immunotherapy and tumour resistance to immune-mediated control and elimination." In Oxford Textbook of Cancer Biology, edited by Francesco Pezzella, Mahvash Tavassoli, and David J. Kerr, 423–37. Oxford University Press, 2019. http://dx.doi.org/10.1093/med/9780198779452.003.0029.
Full textAbstract:
The field of tumour immunology has gradually reached a consensus that the immune system and tumours sustain a rich set of dynamic interactions starting early during carcinogenesis. Incipient tumours may be eliminated by the immune system via adaptive immune responses mediated mainly by cytotoxic CD8 T lymphocytes, which recognize short antigenic peptides presented by polymorphic major histocompatibility complex (MHC) class I molecules. Advanced tumours, however, are generally highly resistant to the main effectors of the immune system. Moreover, the molecular and cellular composition of the tumour microenvironment is strongly immunosuppressive. Recent research efforts have focused on the dissection of the mechanisms operating at the tumour sites, which neutralize antitumour immunity in both experimental models and directly in cancer patients. All along this basic research, translational scientists have tried to harness the immune system to design novel therapeutic modalities that have collectively been coined as cancer immunotherapy. The overall goal has been to increase the numbers of tumour antigen-specific T cells in cancer patients via either vaccination or adoptive transfer of large numbers of immune cells. It is safe to state that cancer immunotherapy will provide a revolution in the treatment of cancer and the future may bear the prospect of effective tumour control in many cancer types, and that immunotherapy will be one of the main components of effective therapeutic options.