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1
Gjerstorff, Morten F., Sofie Traynor, Odd L. Gammelgaard, Simone Johansen, Christina B. Pedersen, Henrik J. Ditzel, and Mikkel G. Terp. "PDX Models: A Versatile Tool for Studying the Role of Myeloid-Derived Suppressor Cells in Breast Cancer." Cancers 14, no. 24 (December 13, 2022): 6153. http://dx.doi.org/10.3390/cancers14246153.
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The pivotal role of myeloid-derived suppressive cells (MDSCs) in cancer has become increasingly apparent over the past few years. However, to fully understand how MDSCs can promote human tumor progression and to develop strategies to target this cell type, relevant models that closely resemble the clinical complexity of human tumors are needed. Here, we show that mouse MDSCs of both the monocytic (M-MDCS) and the granulocytic (PMN-MDSC) lineages are recruited to human breast cancer patient-derived xenograft (PDX) tumors in mice. Transcriptomic analysis of FACS-sorted MDSC-subpopulations from the PDX tumors demonstrated the expression of several MDSC genes associated with both their mobilization and immunosuppressive function, including S100A8/9, Ptgs2, Stat3, and Cxcr2, confirming the functional identity of these cells. By combining FACS analysis, RNA sequencing, and immune florescence, we show that the extent and type of MDSC infiltration depend on PDX model intrinsic factors such as the expression of chemokines involved in mobilizing and recruiting tumor-promoting MDSCs. Interestingly, MDSCs have been shown to play a prominent role in breast cancer metastasis, and in this context, we demonstrate increased recruitment of MDSCs in spontaneous PDX lung metastases compared to the corresponding primary PDX tumors. We also demonstrate that T cell-induced inflammation enhances the recruitment of MDSC in experimental breast cancer metastases. In conclusion, breast cancer PDX models represent a versatile tool for studying molecular mechanisms that drive myeloid cell recruitment to primary and metastatic tumors and facilitate the development of innovative therapeutic strategies targeting these cells.
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Smith, Alyssa D., Chunwan Lu, Daniela Payne, Amy V. Paschall, John David Klement, Priscilla S. Redd, Mohammed Ibrahim, et al. "Autocrine IL6 activates the STAT3-DNMT axis to silence the TNFa-RIP1 necroptosis pathway to sustain myeloid-derived suppressor cell survival and accumulation." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 164.10. http://dx.doi.org/10.4049/jimmunol.204.supp.164.10.
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Abstract Accumulation of myeloid-derived suppressor cells (MDSCs) is a hallmark of cancer. However, the underlying mechanism of MDSC accumulation in the tumor microenvironment (TME) remain incompletely understood. We report that MDSC accumulation is regulated by the TNFα-RIP1-mediated necroptosis. We determined that inhibition of DNMTs with Decitabine (DAC) abolished MDSC accumulation and increased activation of antigen-specific cytotoxic T lymphocytes (CTLs) in tumor-bearing mice. DAC-induced decrease of MDSC accumulation is correlated with increased IRF8 expression in MDSCs. However, DAC also abolished MDSC-like cell accumulation in IRF8 KO mice, indicating that DNA methylation does not regulate MDSC lineage differentiation but mediates MDSC accumulation at post differentiation stage. We determined that DAC decreased MDSC accumulation through increasing cell death and identified RIP1-dependent necroptosis as target of DNA methylation in MDSCs. Genome-wide DNA bisulfite sequencing revealed that the Tnf promoter is hypermethylated in tumor-induced MDSCs in vivo. Consequently, DAC dramatically increased TNFα level in MDSCs and neutralizing TNFα significantly decreased MDSC cell death. Furthermore, recombinant TNFα induced MDSC cell death in a does- and RIP1-dependent manner. IL6 which is expressed in MDSCs in tumor-bearing mice and human colorectal cancer patients. Our data shows that the autocrine IL6 activates the STAT3-DNMT axis to epigenetically silence the TNFα-RIP1 necroptosis pathway to sustain MDSC survival and accumulation in cancer. Targeting the TNFα-RIP1 necroptosis is potentially an effective approach to supress MDSCs to activate tumor-reactive CTLs in the TME.
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Aristova, T. A., E. V. Batorov, V. V. Sergeevicheva, S. A. Sizikova, G. Yu Ushakova, A. V. Gilevich, E. Ya Shevela, A. A. Ostanin, and E. R. Chernykh. "Myeloidderived peripheral blood suppressor cells at haematopoietic stem cell mobilisation in multiple myeloma patients." Russian journal of hematology and transfusiology 66, no. 2 (September 2, 2021): 218–30. http://dx.doi.org/10.35754/0234-5730-2021-66-2-218-230.
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Introduction. Multiple myeloma (MM) is a B-cell malignancy with clonal expansion of plasma cells in bone marrow. Highdose chemotherapy with autologous haematopoietic stem cell transplantation is among main consolidation therapies in MM. Myeloid-derived suppressor cells (MDSCs) are immature myeloid-accompanying cells able to suppress the immune response. The administration of granulocyte colony stimulating factor (G-CSF) to mobilise haematopoietic stem cells (HSCs) increases the MDSC count in peripheral blood (PB).Aim — to study MDSC subsets in PB of remission MM patients and their incidence dynamics at HSC mobilisation.Methods. The study surveyed 35 MM patients prior to and after HSC mobilisation. The counts of granulocytic (G-MDSCs; Lin–HLA-DR–CD33+ CD66b+), monocytic (М-MDSCs; CD14+ HLA-DRlow/–) and early MDSCs (E-MDSCs; Lin–HLA-DR– CD33+ CD66b–) were estimated in flow cytometry.Results. Remission MM patients differed from healthy donors in higher relative counts of G-MDSCs (Lin–HLA-DR– CD33+ CD66b+) and increased relative and absolute counts of М-MDSCs (CD14+ HLA-DRlow/–). М-MDSCs significantly outnumbered G-MDSCs. MDSC subset counts were elevated in complete response (CR) and very good partial response (VGPR), as well as in partial response (PR). Higher relative MDSC counts were associated with greater pretreatment (2–3 lines of chemotherapy). After HSC mobilisation with cyclophosphamide 2–4 g/m2 + G-CSF (filgrastim 5 μg/kg/day), the median relative E-MDSC and M-MDSC counts increased by 2.3 and 2.0 times, respectively, while the relative G-MDSC count raised 46-fold perturbing the MDSC subset balance.Conclusion. Remission MM patients had the increased relative G-MDSC and both relative and absolute M-MDSC counts compared to donors. A greater patient pretreatment was associated with higher relative G-MDSC counts. Treatment response (CR/VGPR vs. PR) was not coupled with MDSC count variation. The G-CSF-induced HSC mobilisation entailed a significant expansion of all three MDSC subsets in PB.
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Green, Kathy, Li Wang, Randolph Noelle, and William Green. "MDSC suppression of B cell responses in murine retrovirus-induced immunodeficiency: a role for VISTA (IRC4P.603)." Journal of Immunology 194, no. 1_Supplement (May 1, 2015): 57.20. http://dx.doi.org/10.4049/jimmunol.194.supp.57.20.
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Abstract Inhibition by myeloid derived suppressor cells (MDSC) of T cell responses is well established in tumor microenvironments. We demonstrated (Green et al., 2013) induction of monocytic MDSCs during infection of B6 mice by LP-BM5 retrovirus, which causes profound immunodeficiency. These MDSCs suppressed not only T, but also B cell, responsiveness ex vivo. Whereas MDSC inhibition of stimulated T cell proliferation and IFN-gamma production was ~100%, iNOS/NO dependent, MDSC suppression of B-cell responses was only ~50% dependent on iNOS/NO - as shown by using iNOS inhibitors and iNOS k.o. mice as a source of MDSCs. We then discovered an additional mechanism(s) in MDSC inhibition of (only) B cell responsiveness that involved VISTA, a new negative checkpoint regulator. Using anti-VISTA blocking mAb, or LP-BM5 infected VISTA-/- MDSCs, MDSC inhibition of B cell responses was dependent on MDSC-expressed VISTA — again accounting for ~50% of total MDSC suppression. Combining the use of reagents to block both iNOS/NO and VISTA lead to an additive, if not synergistic, abrogation of MDSC suppression of B cell responsiveness. Consistent with a direct role of VISTA, in the absence of MDSCs, a VISTA-Ig fusion protein also partially inhibited B cell responsiveness. These results were compatible with a role for MDSC in LP-BM5-induced immunodeficiency and highlight involvement of multiple and unique suppressive pathways in the under-studied area of MDSC suppression of B cell responses.
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Xie, Qifa, Jingwen Zhang, Smita Ghare, Shirish Barve, and Craig McClain. "CD11b+/Gr-1int monocytic myeloid derived suppressor cells contribute to high-fat induced inflammation and delayed tolerance in mouse liver (54.15)." Journal of Immunology 186, no. 1_Supplement (April 1, 2011): 54.15. http://dx.doi.org/10.4049/jimmunol.186.supp.54.15.
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Abstract Myeloid derived suppressor cells (MDSC) are a heterogeneous population of immature myeloid cells with universal expansion in nearly all inflammatory conditions. This study investigated the accumulation of MDSC in chronic inflammation and tolerance of obesity-related fatty liver disease. We found that the expansion of MDSC, specifically associated with the monocytic MDSC (M-MDSC): CD11b+Gr-1intLy6G-Ly6Chigh in the liver of B6 mice fed a high-fat diet contributes to liver inflammation and tolerance. M-MDSCs isolated from the liver of obese mice are more easily activated by way of Toll-like receptor (TLR4) stimulation resulting in inflammatory cytokine expression, and were functional MDSCs, readily inhibiting T cell proliferation in vitro dependent on cell-cell contact between MDSCs and T cells. The rapid accumulation of M-MDSC also contributed to delayed ConA tolerance in obesity-related fatty liver disease. M-MDSCs isolated from the liver of obese mice developed with ConA tolerance induce less liver regulatory T (Treg) cell expansion and less suppressing T cell proliferation in vitro. Experiments using mice depleted of Gr-1, or M- MDSC adoptive transfer demonstrated the important role of M-MDSC in liver inflammation and tolerance. These data unveil that M-MDSCs play an essential negative feedback function in liver immune homeostasis.
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Park, Young-Jun, Boyeong Song, Yun-Sun Kim, Eun-Kyung Kim, Jung-Mi Lee, Ga-Eun Lee, Jae-Ouk Kim, Yeon-Jeong Kim, Woo-Sung Chang, and Chang-Yuil Kang. "Myeloid derived suppressor cells(MDSCs) emergence from distinct splenic precursors (162.28)." Journal of Immunology 188, no. 1_Supplement (May 1, 2012): 162.28. http://dx.doi.org/10.4049/jimmunol.188.supp.162.28.
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Abstract Myeloid derived suppressor cells(MDSCs) are a heterogenous population of immature myeloid cells, which accumulate in various pathological conditions, especially in tumor. In mice, MDSCs are characterized by the co-expression of Gr1 and CD11b molecules, and these cells could be classified into two subsets, CD11b+Ly6G+Ly6Clow polymorphonuclear neutrophil-like(PMN) MDSCs and CD11b+Ly6G-Ly6Chigh monocytic(Mo) MDSCs, by their expression of Ly6C and Ly6G molecules. Functional characteristics and fate of MDSCs are defined quite well. On the other hands, accumulation mechanism and origins of MDSC need to be more elucidated, and have not been fully understood whether MDSC could be generated in the periphery from distinct precursors in tumor microenvironment. For the first time, we identified the presence of splenic MDSC precursors in tumor bearing mice, characterized by CD11b+Ly6G-Ly6Cneg/low. We demonstrated that cytokines related to MDSC accumulation convert CD11b+Ly6G-Ly6Cneg/low cells into CD11b+Ly6G+Ly6Clow PMN-MDSC and/or CD11b+Ly6G-Ly6Chigh Mo-MDSC. These converted cells exerted strong suppressive activity on DO11.10 Tg splenocytes proliferation. Thus, these data suggest that there are peripheral distinct precursors, CD11b+Ly6Cneg/low cells, from which immunosuppressive MDSC could be generated.
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Li, Xing, Qing-Jian Ye, Yan-Fang Xing, Jin-Xiang Lin, Qu Lin, and Xiang-yuan Wu. "Expansion of Lox-1+CD15+ myeloid-derived suppressor cells in hepatocellular carcinoma patients." Journal of Clinical Oncology 35, no. 7_suppl (March 1, 2017): 124. http://dx.doi.org/10.1200/jco.2017.35.7_suppl.124.
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124 Background: The top issue in the field of myeloid deprived suppressor cell (MDSC) was lack of specific markers. Lox-1 was reported to be a novel marker for polymorphonuclear MDSC (PMN-MDSC) in whole blood of head and neck cancer and lung cancer patients. The present study is aimed to detecting the lox-1 PMN-MDSC in whole blood. Methods: In the present study, a series of 24 hepatocellular carcinoma (HCC) patients and 12 healthy donors were analyzed investigating frequencies of PMN-MDSC (Lox-1+CD15+) in whole blood. The immunosuppressive function of MDSC were evaluated using T cell proliferation and activation tests. The underly mechnisms were determined using inhibitors, genes expression and activity tests. The association between MDSC and clinical parameters were determined retrospectively. Results: Patients presented significantly higher level of PMN-MDSCs. In order to confirm immune suppressive capacity of PMN-MDSCs in HCC patients, circulative PMN-MDSCs and T cells were purified using flow sorting and cocultured. T cell proliferation was abrogated by the addition of PMN-MDSC with a dosage dependent manner, as well as the production of IFN-γ. Besides, the suppression on T cell proliferation and IFN-γ production was partially reversed by reactive oxygen species (ROS) inhibitor and Arginase inhibitor. The ROS level were higher in PMN-MDSC than their normal controls. The mRNA level of NOX2, the key protein complex responsible for ROS productin in MDSC, and Arginase I were higher in PMN-MDSCs. Finally, the frequencies of PMN-MDSCs was positively associated with tumor volume. Conclusions: The present study found that Lox-1+CD15+ were novel markers for PMN-MDSCs in whole blood and very easily to be standardized between institutions.
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Green, Kathy A., Randolph J. Noelle, William R. Green, and Li Wang. "Checkpoint Regulator VISTA plays a role in Suppression of B-Cell Responsiveness by Monocytic Myeloid Derived Suppressor Cells from LP-BM5 retrovirus-infected Mice." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 195.14. http://dx.doi.org/10.4049/jimmunol.196.supp.195.14.
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Abstract MDSC inhibition of tumor directed T cell responses is well described. We have reported an increase of monocytic MDSC (M-MDSC) during infection of B6 mice by LP-BM5 immunodeficiency causing retrovirus. These M-MDSCs suppressed T, and B cell responsiveness ex vivo. M-MDSC inhibition of stimulated T-cell proliferation and IFN-gamma production was ~100% iNOS/NO dependent; whereas suppression of B-cells was only ~50% dependent on iNOS/NO. An additional mechanism(s) for M-MDSC inhibition of B cell responsiveness involved V-domain Ig Suppressor of T cell Activation (VISTA), negative checkpoint regulator. Using anti-VISTA blocking mAb, ~50% of total MDSC suppression of B-cell responses was dependent on MDSC-expressed VISTA. The combination of iNOS/NO inhibitors and VISTA lead to additive, if not synergistic, blockade of M-MDSC suppression of B cell responsiveness. Regarding the LP-BM5-infection dependency of M-MDSCs, spleens from uninfected mice yielded ~3-fold fewer enriched M-MDSCs; and on a per-cell basis, the M-MDSCs from uninfected mice were also substantially less suppressive (4.3 fold); than those from infected mice. Consistent with a direct role of VISTA, in the absence of M-MDSCs, a VISTA-Ig fusion protein also partially inhibited B-cell responsiveness. Initial experiments show differential VISTA expression for the LP-BM5 M-MDSC CD11b+hiLy6C+hi subpopulations we have recently defined (O’Connor et al, 2015, Virology). Thus, LP-BM5 infected, when compared to analogous subsets from uninfected mice, contain substantially more VISTA+ cells. These results suggest an unique role for M-MDSCs in LP-BM5 induced immunodeficiency, and highlight multiple suppressive pathways in the area of MDSC suppression of B cell responses.
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Green, Kathy, Li Wang, and William Green. "Suppression of B cell responsiveness by LP-BM5 retrovirus-induced myeloid derived suppressor cells generated during a murine acquired immunodeficiency syndrome: a role for negative checkpoint regulator expression on the MDSCs (VIR7P.1059)." Journal of Immunology 192, no. 1_Supplement (May 1, 2014): 208.11. http://dx.doi.org/10.4049/jimmunol.192.supp.208.11.
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Abstract The inhibitory activities of myeloid derived suppressor cells (MDSC) against T cell responses are well established in tumor microenvironments. We published (2013, J. Virol. 87:2058-2071) on the induction of monocytic MDSCs during infection of susceptible B6 mice by LP-BM5 retrovirus, which causes a profound immunodeficiency. These MDSCs inhibited not only T, but also B cell, responsiveness to polyclonal stimulation in ex vivo suppression assays. Whereas MDSC inhibition of stimulated T cell proliferation and IFN-gamma production was largely iNOS/NO dependent, MDSC suppression of B cell responses was only partially (~50%) due to iNOS/NO - as shown by using iNOS inhibitors and LP-BM5 infected iNOS k.o. mice as a source of MDSCs. Here, we further study additional suppressive mechanism(s) in the MDSC inhibition of B cell responsiveness. Using MDSCs from LP-BM5 infected mice of negative checkpoint regulator knock-out origin, and specific blocking antibody, MDSC suppression of B cell responses was partly dependent on MDSC expression of certain checkpoint regulators. Combining the use of reagents to interrupt both iNOS/NO and checkpoint regulation lead to a synergistic blocking of MDSC suppression of B cell responsiveness. These results were compatible with a role for MDSC in LP-BM5 induced immunodeficiency and highlight the involvement of multiple and unique suppressive pathways in the under-studied area of MDSC suppression of B cell responses.
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Fallah, Jaleh, C. Marcela Diaz-Montero, Patricia A. Rayman, Wei (Auston) Wei, Iris Yeong Fung Sheng, James Finke, Jin Sub Kim, et al. "Correlation of myeloid-derived suppressor cells (MDSC) with pathologic complete response (pCR), recurrence free survival (RFS), and overall survival (OS) in patients with urothelial carcinoma (UC) undergoing cystectomy." Journal of Clinical Oncology 37, no. 7_suppl (March 1, 2019): 437. http://dx.doi.org/10.1200/jco.2019.37.7_suppl.437.
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437 Background: MDSCs play an important role in maintaining a tumor immunosuppressive microenvironment. The association of circulating levels of MDSCs with pCR (pT0N0) and outcomes was investigated in patients (pts) with non-metastatic UC undergoing cystectomy. Methods: Peripheral blood samples from pts with non-metastatic UC was collected. MDSCs were measured in freshly purified peripheral blood mononuclear cells, using flow cytometry. Total (T) MDSC was defined as CD33+/HLADR-. T-MDSC subtypes were polymorphonuclear (PMN-MDSC: CD15+/CD14-), monocytic (M-MDSC: CD15-/CD14+], and uncommitted (UC-MDSC: CD15-/CD14-]. MDSC populations were presented as % of live nucleated blood cells. Wilcoxon rank sum test was used to compare MDSCs between pCR groups. Kaplan-Meier and log-rank test were used to analyze RFS and OS. Results: MDSC data were available for 124 pts (106 male, 18 female), median age 68, 28 (23%) never smokers, 93 (75%) pure UC. Thirty four pts (27%) received intravesical BCG; 49 (39%) received neoadjuvant chemotherapy (NAC); 22 (19%) had pCR (pT0N0) following surgery. PMN-MDSC was the dominant subtype (42%) and frequency of UC-MDSC and M-MDSC was 40% and 17%, respectively. Circulating levels of T-MDSC and PMN-MDSC were significantly lower in pCR patients than those in non-pCR patients (Table). Sixteen deaths were observed and 21 pts recurred after surgery. The median follow-up time of patients alive was 18.7 months (range 0.3-42.4). The median OS or RFS of all patients was not reached. One-year and two-year OS rates were 94% and 83%, respectively. One-year and two-year RFS rates were 82% and 69%, respectively. There was no association between MDSC subtypes with OS or RFS. Conclusions: Total- and PMN-MDSC subtypes in blood were significantly correlated with pCR in pts with non-metastatic UC who undergo cystectomy. The relatively short follow-up may impact the association with RFS and OS; additional follow-up is needed. [Table: see text]
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Mabuchi, Seiji, Tomoyuki Sasano, and Naoko Komura. "Targeting Myeloid-Derived Suppressor Cells in Ovarian Cancer." Cells 10, no. 2 (February 5, 2021): 329. http://dx.doi.org/10.3390/cells10020329.
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Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells that exhibit immunosuppressive activity. They also directly stimulate tumor cell proliferation, metastasis, and angiogenesis. In ovarian cancer, there are increased numbers of circulating or tumor-infiltrating MDSCs, and increased frequencies of MDSCs are associated with a poor prognosis or an advanced clinical stage. Moreover, in murine models of ovarian cancer, MDSC depletion has shown significant growth-inhibitory effects and enhanced the therapeutic efficacy of existing anticancer therapies. In this review, we summarize the current knowledge on MDSC biology, clinical significance of MDSC, and potential MDSC-targeting strategies in ovarian cancer.
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Liu, Tianju, Andrew Rinke, Kevin Flaherty, and Sem Hin Phan. "Potential role of myeloid-derived suppressor cells in pulmonary fibrosis." Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 182.3. http://dx.doi.org/10.4049/jimmunol.202.supp.182.3.
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Abstract Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease without effective curative therapy. Recruitment of bone marrow-derived myeloid cells is implicated in lung fibrosis by promoting fibrosis via paracrine mechanisms. Recent evidence shows increased circulating myeloid-derived suppressor cells (MDSC) in IPF patients. More recently, the importance of MDSC is suggested by the observation of MDSC accumulation in IPF lungs. The objective of this study was to assess the accumulation/expansion of MDSC in bleomycin-induced mouse model of pulmonary fibrosis and human IPF, and investigate their potential role in lung myofibroblast differentiation. Flow cytometry analysis showed that MDSCs in lung were increased in a mouse model of lung fibrosis, as well as in peripheral blood samples from IPF patients. The increase of the monocytic subtype of MDSC (M-MDSC) was greater than that for the granulocytic subtype (G-MDSC) in the peripheral blood samples from patients with IPF. In vitro co-culture of normal mouse lung fibroblasts with sorted bone marrow (BM)-derived MDSCs using trans-well inserts revealed paracrine activation of lung fibroblasts by activated M-MDSC, but not GMDSC, as manifested by significantly elevated mRNA levels of α-smooth muscle actin and TGFβ mRNAs. Both quiescent M-MDSC and G-MDSC failed to stimulate fibroblast activation or myofibroblast differentiation. Interestingly, the level of TGFβ mRNA in M-MDSC was higher than G-MDSC. These findings indicated that in pulmonary fibrosis, BM-derived MDSCs were mobilized and recruited to the lung, and the recruited M-MDSC subpopulation subsequently played a paracrine role by activating resident lung fibroblasts and myofibroblast differentiation.
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Thevenot, Paul, Rosa Sierra, Patrick Raber, Amir Al Khami, Augusto Ochoa, and Paulo Rodriguez. "C/EBP homologous protein expression regulates immunosuppressive activity in myeloid derived suppressor cells (TUM6P.1006)." Journal of Immunology 194, no. 1_Supplement (May 1, 2015): 141.30. http://dx.doi.org/10.4049/jimmunol.194.supp.141.30.
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Abstract Myeloid-derived suppressor cell (MDSC) suppression of anti-tumor T cell responses is a significant barrier in cancer immunotherapy. Although pathways controlling MDSC regulatory activity have been characterized, therapies to globally and specifically inhibit MDSC function are limited. Targeting central mediators of MDSC-regulatory activity may overcome T cell suppression and increase the efficacy of T cell-based immunotherapy. We investigated the role of the stress sensor C/EBP homologous protein (Chop) on MDSC function. Elevated Chop expression in tumor-bearing mice was restricted to malignant cells and tumor MDSCs. Chop elevation was also detected in tumor MDSCs from colon carcinoma patients. Interestingly, increased CD8+ T cell-mediated anti-tumor effects were found in both systemic Chop -/- and Chop -/- bone marrow chimeric mice bearing s.c. Chop-competent tumors, suggesting the importance of MDSC-Chop in tumor-induced T cell anergy. MDSCs from Chop -/- mice showed a decreased expression of major MDSC-inhibitory pathways, reduced inhibitory activity on T cells, and a surprising ability to prime T cell proliferation and induce anti-tumor effects. The reduced regulatory activity in Chop -/- MDSCs was caused by decreased IL-6 production, resulting from decreased C/EBPb activity. Altogether the results demonstrate a central role of Chop in MDSC inhibitory activity and suggest targeting Chop to restore protective immunity in cancer.
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Jalali, Shahrzad, Jose Villasboas, Jie Shi, Cole Bothun, Hyojin Kim, Zhi-Zhang Yang, and Stephen M. Ansell. "Mass Cytometry Identifies a Novel Signature for Myeloid-Derived Suppressor-Cells in Waldenstrom's Macroglobulinemia." Blood 134, Supplement_1 (November 13, 2019): 3976. http://dx.doi.org/10.1182/blood-2019-124850.
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Myeloid derived suppressor cells (MDSC) are a heterogeneous population of undifferentiated myeloid cells that are expanded and activated in pathological conditions and have the ability to potently suppress T-cell function and thereby contribute to immunosuppression and tumor progression. While there have been studies showing a role for MDSC in a variety of hematological malignancies, no data is available indicating that MDSCs contribute to the tumor progression in Waldenstrom's Macroglobulinemia (WM), an indolent lymphoma characterized by bone marrow (BM) infiltration of lymphoplasmacytic (LPL) cells and increased secretion of monoclonal IgM. In previous work, we have found increased GM-CSF and reduced arginine and cysteine in the BM microenvironment in WM. We hypothesized that this was due to the presence and activity of MDSCs in WM. BM aspirates from WM patients (n=17) were therefore processed to isolate LPL (CD19+/CD138+) cells from the rest of the BM cells (CD19-/CD138-). Sorted (CD19-/CD138-) cells from BM of patients with WM were studied with flow cytometry. Using a sequential gating strategy (lack of lineage markers, low levels of HLADR, CD33+, CD11b+) we identified a population of MDSCs that were then subdivided using CD14 and CD15 expression into total-, monocytic-, or granulocytic- MDSCs (m-MDSC, g-MDSC). We also analyzed unsorted BM cells using cytometry by time-of-flight (CyTOF) in order to further identify and phenotypically characterize the BM MDSC population in a group of WM patients with smoldering (asymptomatic) disease, symptomatic disease, or in remission post-treatment. BM samples from normal subjects were used as a control. Flow cytometry data showed significant higher numbers of MDSC subsets expressing PD-L1 and Arginase1 in WM patients when compared to the normal samples. BM cells from WM patients (n=18) then were compared to controls (n=11), and the absolute number of the total MDSC (p=0.05), m-MDSC (p=0.002), g-MDSC (p=0.02) was increased in WM specimens. When MDSCs from WM or normal monocytes from healthy controls were co-cultured with activated T-cells, the proliferation of activated T-cells in the presence of MDSCs from WM patients was impaired compared to controls, confirming the suppressive role of MDSCs. We then performed high dimensional analysis of the total BM MDSC cells using t-SNEand identified phenotypically distinct MDSC cell populations in the BM that were differentially present when healthy controls were compared to patients with smoldering WM or those with WM needing treatment. Specifically, WM patients needing treatment had increased numbers of a distinct MDSC population that was highly positive for CD163, and CD138. Moreover, conventional markers denoting m-MDSC and g-MDSC, such as CD14 and CD15, were highly expressed in all populations and their pattern of expression did not specifically define the MDSC subtypes, indicating that high dimensional phenotyping further details the MDSC sub-compartments beyond the conventional categorization of MDSC using conventional cytometry. In summary, we find that MDSCs are increased in the BM of WM patients compared to controls. MDSCs expressing CD163 and CD138 increase when WM patients become symptomatic and require therapy. Furthermore, MDSCs in the BM of WM patients suppress T-cell function and likely contribute to progression of the disease. MDSCs in the BM therefore present a therapeutic target that should be explored in WM patients. Disclosures Ansell: Bristol Myers Squibb: Other: research funding for clinical trials; Merck: Other: research funding for clinical trials; AI Therapeutics: Other: research funding for clinical trials; Affimed: Other: research funding for clinical trials; Takeda: Other: research funding for clinical trials; Pfizer: Other: research funding for clinical trials; Regeneron: Other: research funding for clinical trials; Seattle Genetics: Other: research funding for clinical trials.
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Movahedi, Kiavash, Martin Guilliams, Jan Van den Bossche, Rafael Van den Bergh, Conny Gysemans, Alain Beschin, Patrick De Baetselier, and Jo A. Van Ginderachter. "Identification of discrete tumor-induced myeloid-derived suppressor cell subpopulations with distinct T cell–suppressive activity." Blood 111, no. 8 (April 15, 2008): 4233–44. http://dx.doi.org/10.1182/blood-2007-07-099226.
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Abstract The induction of CD11b+Gr-1+ myeloid-derived suppressor cells (MDSCs) is an important immune-evading mechanism used by tumors. However, the exact nature and function of MDSCs remain elusive, especially because they constitute a heterogeneous population that has not yet been clearly defined. Here, we identified 2 distinct MDSC subfractions with clear morphologic, molecular, and functional differences. These fractions consisted of either mononuclear cells (MO-MDSCs), resembling inflammatory monocytes, or low-density polymorphonuclear cells (PMN-MDSCs), akin to immature neutrophils. Interestingly, both MO-MDSCs and PMN-MDSCs suppressed antigen-specific T-cell responses, albeit using distinct effector molecules and signaling pathways. Blocking IFN-γ or disrupting STAT1 partially impaired suppression by MO-MDSCs, for which nitric oxide (NO) was one of the mediators. In contrast, while IFN-γ was strictly required for the suppressor function of PMN-MDSCs, this did not rely on STAT1 signaling or NO production. Finally, MO-MDSCs were shown to be potential precursors of highly antiproliferative NO-producing mature macrophages. However, distinct tumors differentially regulated this inherent MO-MDSC differentiation program, indicating that this phenomenon was tumor driven. Overall, our data refine tumor-induced MDSC functions by uncovering mechanistically distinct MDSC subpopulations, potentially relevant for MDSC-targeted therapies.
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Highfill, Steven L., Paulo C. Rodriguez, Qing Zhou, Christine A. Goetz, Brent H. Koehn, Rachelle Veenstra, Patricia A. Taylor, et al. "Bone marrow myeloid-derived suppressor cells (MDSCs) inhibit graft-versus-host disease (GVHD) via an arginase-1–dependent mechanism that is up-regulated by interleukin-13." Blood 116, no. 25 (December 16, 2010): 5738–47. http://dx.doi.org/10.1182/blood-2010-06-287839.
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Abstract Myeloid-derived suppressor cells (MDSCs) are a well-defined population of cells that accumulate in the tissue of tumor-bearing animals and are known to inhibit immune responses. Within 4 days, bone marrow cells cultured in granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor resulted in the generation of CD11b+Ly6GloLy6C+ MDSCs, the majority of which are interleukin-4Rα (IL-4Rα+) and F4/80+. Such MDSCs potently inhibited in vitro allogeneic T-cell responses. Suppression was dependent on L-arginine depletion by arginase-1 activity. Exogenous IL-13 produced an MDSC subset (MDSC-IL-13) that was more potently suppressive and resulted in arginase-1 up-regulation. Suppression was reversed with an arginase inhibitor or on the addition of excess L-arginine to the culture. Although both MDSCs and MDSC-IL-13 inhibited graft-versus-host disease (GVHD) lethality, MDSC-IL-13 were more effective. MDSC-IL-13 migrated to sites of allopriming. GVHD inhibition was associated with limited donor T-cell proliferation, activation, and proinflammatory cytokine production. GVHD inhibition was reduced when arginase-1-deficient MDSC-IL-13 were used. MDSC-IL-13 did not reduce the graft-versus-leukemia effect of donor T cells. In vivo administration of a pegylated form of human arginase-1 (PEG-arg1) resulted in L-arginine depletion and significant GVHD reduction. MDSC-IL-13 and pegylated form of human arginase-1 represent novel strategies to prevent GVHD that can be clinically translated.
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Morenkova, A., M. Tikhonova, T. Tyrinova, E. Batorov, A. Sizikov, O. Chumasova, A. Sulutian, V. Koksharova, D. Orlov, and E. Chernykh. "AB0059 CLINICAL SIGNIFICANCE OF CIRCULATING MYELOID-DERIVED SUPPRESSOR CELLS IN PATIENTS WITH ANKYLOSING SPONDYLITIS." Annals of the Rheumatic Diseases 79, Suppl 1 (June 2020): 1331.1–1331. http://dx.doi.org/10.1136/annrheumdis-2020-eular.2998.
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Background:Myeloid-derived suppressor cells (MDSCs) represent heterogeneous population of immature myeloid cells with immunosuppressive functions. The important role of MDSCs is indicated for cancer, but their role in autoimmune pathology is currently controversial. Considering the clinical heterogeneity of ankylosing spondylitis (AS) and involvement of innate immunity in AS pathophysiology the investigation of the MDSC role in AS is of great interest.Objectives:The aim of our study is to investigate the number of MDSC subsets in AS patients with different clinical manifestations, activity, disease duration, and treatment options and to evaluate the ability of MDSCs to mediate immunosuppressive function in AS patients.Methods:The study included 34 patients with AS. Ankylosing Spondylitis Disease Activity Score (ASDAS) was used to assess disease activity and high activity was determined as ASDAS≥2.1. The frequencies of monocytic (M-MDSC) (HLADR-CD14 +), granulocytic (G-MDSC) (lin-HLADR-CD33+ CD66 +) and early-stage (eMDSC) (lin-HLADR-CD33 + CD66-) MDSCs and biomarkers of MDSCc functional activity including of Arg-1, IDO, PDL1 were determined in the peripheral blood by flow cytometry.Results:We found significant elevation in the frequency of both M-MDSC and G-MDSC in the total group of patients compared to healthy controls (HC) (P=0.00006 and P=0.008 respectively), while eMDSCs did not differ from HC. Analysis of MDSCs populations in patient subgroups showed expansion of G-MDSCs in patients with axial plus peripheral damages (P=0.004), while M-MDSCs were elevated regardless of the presence (P=0.002) or absence (P=0.001) of peripheral manifestations. Moreover, the percentage of M-MDSCs was positively correlated with ASDAS in patients with axial disease only (R=0.8; P=0.03). Patients with low activity of disease demonstrated significant elevation of only M-MDSCs compared with HC (P=0.001). Patients who had high activity of disease had increase in both M-MDSCs and G-MDSCs (P=0.008 and P=0.005 respectively). By comparing the frequency of MDSCs in patient groups with different AS duration we showed increase in percentage of both M-MDSCs and G-MDSCs in patients with relatively short duration of disease (< Me=11.5 years) (P=0.002 and P=0.005 respectively) and elevation in M-MDSCs only in patients with longer AS duration (P=0.0003). Compared with patients receiving conventional therapy (NSAIDs, csDMARDs), patients who received biological agents (TNFα inhibitors) had lower disease activity but despite this showed elevated frequencies of M-MDSCs and PMN-MDSCs, comparable to patients receiving conventional therapy. Of note, M-MDSCs in AS patients had increased expression of PDL-1 and IDO (P=0.04 and P=0.02 respectively) and similar to HC expression of Arg-1. The expression of Arg-1, IDO, PDL1 in patients G-MDSCs did not differ from HC.Conclusion:The data obtained indicate that both M-MDSCs and G-MDSCs are elevated in AS patients. However, the increase of G-MDSCs is associated with peripheral manifestations of AS, high activity, longer duration, and the percentage of M-MDSCs was positively correlated with activity in patients with axial disease only. The unchanged expression of Arg-1, PDL-1 and IDO in G-MDSCs and enhanced expression of PDL-1 and IDO in M-MDSCs suggest MDSCs capacity to mediate immunosuppressive function in AS patients.Disclosure of Interests:None declared
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Sheng, Iris Yeong Fung, C. Marcela Diaz-Montero, Patricia A. Rayman, Wei (Auston) Wei, Jaleh Fallah, James Finke, Jin Sub Kim, et al. "Blood myeloid derived suppressor cells (MDSC) in metastatic urothelial carcinoma (mUC) are correlated with neutrophil-to-lymphocyte ratio (NLR) and overall survival (OS)." Journal of Clinical Oncology 37, no. 7_suppl (March 1, 2019): 436. http://dx.doi.org/10.1200/jco.2019.37.7_suppl.436.
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436 Background: MDSC have been linked to the chronic inflammatory microenvironment of tumor cells and pathologic outcomes in UC patients (pts) undergoing cystectomy. NLR is an established inflammatory biomarker with prognostic properties in mUC. We hypothesized that MDSCs correlate with NLR and OS in mUC. Methods: MDSCs were measured in blood samples from mUC patients by fresh unfractionated whole blood (WB) and peripheral blood mononuclear cells (PBMC). MDSCs were identified by flow cytometry in WB and defined as LinloCD33+/HLADR- (Total MDSC). MDSC subsets were defined as polymorphonuclear (PMN-MDSC: CD15+/CD14-), monocytic (M-MDSC: CD15-/CD14+), and uncommitted (UC-MDSC: CD15-/CD14-). MDSC populations were presented as % of live nucleated blood cells from PB and absolute numbers from WB. Spearman’s correlation assessed correlations between MDSC & NLR. Kaplan Meier curves and log rank test estimated OS from the time of MDSC collection to last follow up or date of death. Results: Of 79 pts, 77% were men and 42% were never smokers with a median age of 69 (31-83). Overall, 71% had pure UC and 81% had lower tract UC. Prior therapies include intravesical therapy (22%), neoadjuvant chemotherapy (31%), and cystectomy/nephroureterectomy (61%). Median follow up was 12 months (range: 0.6-36.5). PMN-MDSC was the predominant subset in WB and PBMC. There was significant correlation between individual MDSC subsets in WB and PBMC (p≤0.001). Negative correlation was noted between NLR and WB UC-MDSC:PMN-MDSC ratios (rho = -0.27, p = 0.03), as well as NLR and PB UC-MDSC:PMN-MDSC (rho = -0.28, p = 0.02). Median survival was 17.7 months (95% CI: 11.0-NA months). Overall 1-yr and 3-yr survival were 0.60 (95% CI: 0.49-0.73) and 0.15 (95% CI: 0.03-0.67), respectively. Higher WB UC-MDSC levels were associated with shorter OS (HR 2.85, 95% CI: 1.43-5.65, p = 0.003). Conclusions: Specific MDSC subsets correlate with NLR. Higher WB UC-MDSC levels have negative prognostic roles for OS. Given the feasibility of serial blood draws, dynamic assessment of MDSC over time and further validation with longer follow up are needed.
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Vetsika, E., Marianthi Gioulmpasani, Eirini Skalidaki, Afroditi Katsarou, Filippos Koinis, Despoina Aggouraki, Anna Koutoulaki, Dimitris Mavroudis, Vassilis Georgoulias, and Athanasios Kotsakis. "Effect of chemotherapy on the myeloid-derived suppressor cells percentages in the peripheral blood of advanced non-small cell lung cancer patients (TUM6P.965)." Journal of Immunology 194, no. 1_Supplement (May 1, 2015): 141.13. http://dx.doi.org/10.4049/jimmunol.194.supp.141.13.
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Abstract In our previous study, high levels of one granulocytic (G-MDSC) and two monocytic (M-MDSCs) subpopulations of immunosuppressive MDSCs were found and their overexpression was correlated with worse prognosis in NSCLC patients. Using flow cytometry, the impact of chemotherapy on the percentages and functionality of M-MDSC (CD14+CD15-CD11b+CD33+HLA-DR-Lin- and CD14+CD15+CD11b+ CD33+HLA-DR-Lin-) and G-MDSC (CD14-CD15+CD11b+CD33+HLA-DR-Lin-) was evaluated in the peripheral blood of patients (n=141) prior to chemotherapy and after the 3rd and 6th cycle of treatment. The M-MDSC (CD14+CD15-CD11b+CD33+HLA-DR-Lin-) percentages were found significantly decreased post chemotherapy compared to baseline, whereas chemotherapy had no effect on CD14+CD15+CD11b+CD33+HLA-DR-Lin- M-MDSCs. In contrast, the production of iNOS by M-MDSCs was significantly increased compared to the baseline. Both G-MDSC levels and their ROS expression were not affected by chemotherapy. In addition, both subtypes of MDSCs, when co-cultured with CD3+ T cells, were able to significantly suppress IFN-γ secretion by T cells. Finally, the M-MDSC (CD14+CD15-CD11b+CD33+HLA-DR-Lin-) percentages were found significantly decreased in patients that did not develop progressive disease during or after treatment completion, compared to patients with disease progression. Chemotherapy seems to have an impact on MDSC expression and functionality, hence targeting these cells may lead to a better clinical outcome in NSCLC patients.
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Bian, Zhen, Lei Shi, and Yuan Liu. "Identification of CXCR2 as an important regulator of granulocytic myeloid-derived suppressor cell mobilization during tumor progression (TUM4P.912)." Journal of Immunology 192, no. 1_Supplement (May 1, 2014): 138.13. http://dx.doi.org/10.4049/jimmunol.192.supp.138.13.
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Abstract Expansion of myeloid-derived suppressor cells (MDSCs) is associated with cancer progression and suppression of T cell function. However, further defining MDSCs and their role is hindered by the fact that no specific cell marker is available to distinguish MDSCs from non-suppressive leukocytes. Here we report a separation method that clearly separate granulocytic MDSC (G-MDSC) from non-suppressive granulocytes. In this study, mouse bone marrow cells from healthy and tumor bearing mice were collected, followed by Percoll density gradients centrifugation. Naive CD11b+Ly6G+Ly6Clow granulocytes from the fraction between 50-60% Percoll effectively inhibited the proliferation of T cells via production of ROS and arginase. These suppressive cells were expanded during tumor formation and the inhibitory function was enhanced in tumor bearing mice, indicating that G-MDSC was enriched at the 50-60% Percoll interface. Unlike G-MDSC, high density granulocyte (~60-70% Percoll fraction) failed to suppress T cells proliferation but had a high phagocytic activity and chemotatic capacity toward CXCL1, suggesting that they were mature neutrophils. Further study found that CXCR2 in G-MDSC from tumor bearing mice was significantly upregulated, leading to a massive migration of G-MDSC into spleen and tumor site. Collectively, our findings provide a new way to discriminate G-MDSC from mature granulocytes and reveal a critical role of CXCR2 in G-MDSC mobilization during tumor formation.
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Paschall, Amy V., Priscilla Redd, Ruihua Zhang, Huabao Xiong, Scott I. Abrams, and Kebin Liu. "IRF8 represses GM-CSF expression in tumor cells to mediate myeloid-derived suppressor cell differentiation." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 211.10. http://dx.doi.org/10.4049/jimmunol.196.supp.211.10.
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Abstract Myeloid-derived suppressive cells (MDSCs) are immature myeloid cells that are induced by inflammatory mediators. Massive accumulation of MDSCs is a hallmark of cancer in mice and human patients. Proinflammatory factors are believed to induce MDSC differentiation. In an early study, we showed that T cell-produced GM-CSF, a proinflammatory cytokine, induces MDSC accumulation under physiological conditions. We further determined that IRF8 represses MDSC accumulation in vivo. Tumor cells are known to produce abundant GM-CSF; we therefore sought to test the hypothesis that IRF8 regulates GM-CSF expression to mediate MDSC accumulation in the tumor-bearing host. We observed that mouse sarcoma cells rapidly induce MDSC accumulation, which is positively correlated with tumor growth kinetics. Analysis of purified MDSCs from tumor-bearing mice indicated that GM-CSF mRNA levels increase and IRF8 expression decreases as tumor sizes increase. GM-CSF and IRF8 expression kinetics are therefore inversely correlated in MDSCs in vivo. Analysis of the csf2 gene promoter DNA sequence identified an IRF8-binding consensus element, and ChIP analysis determined that IRF8 binds to this DNA element in the csf2 promoter. Analysis of human sarcoma specimens revealed that the IRF8 promoter DNA is hypermethylated. Silencing IRF8 expression using IRF8-specific shRNA increased GM-CSF expression. In summary, we determine that tumor cells use GM-CSF to induce MDSC differentiation, and IRF8 functions as a transcriptional repressor of GM-CSF expression to suppress MDSC accumulation. Human sarcoma cells may use DNA methylation to silence IRF8 and increase GM-CSF expression to promote MDSC accumulation, thereby suppressing the anti-tumor immune response.
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Wang, Jen-Chin, Chi Chen, Vladimir Gotlieb, Sos Nalghranyan, Ching Wong, and Isabel Yeo. "Elevated Levels of PD-L1 on MDSCs in Patients with Ph(-) Myeloproliferative Neoplasm." Blood 138, Supplement 1 (November 5, 2021): 4591. http://dx.doi.org/10.1182/blood-2021-148260.
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Abstract Introduction. We previously reported that PD-1 and PD-L1 were increased in patients with Ph(-) myeloproliferative neoplasm (MPN) ( Wang et al., Leuk Res 2019). The PD-1 inhibitor therapy or immune checkpoint inhibitor therapy (ICI) trial in MPN by Hobbs et al. reported a negative result (Blood, 2020 (supplement )). Resistance to ICI therapy has been reported to be related to myeloid-derived suppressor cells (MDSCs) in melanoma and breast carcinoma. We also previously reported that MDSCs were increased in patients with Ph(-) MPN (Wang et al., Leu Res 2016). Regulation of immune suppression by MDSCs has been reported to be related to PD-1and PD-L1 expression on the MDSC. Therefore, the current study measured PD-1 and PD-L1 expression in MDSCs in patients with Ph(-) MPN. Materials and Methods. Twenty-six patients, including 11 essential thrombocythemias (ETs), six polycythemia vera (PV), and nine myelofibrosis (six primary MF, one post-ET-MF, two post-PVMF) were compared with ten normal volunteer controls. MDSCs were measured as follows: the pelleted PBMNCs were used for Magnetic-assisted cell separation (MACS, Miltenyi Biotech, Inc.). PBMNCs are sequentially selected for HLA-DR - cells, from which we further selected for CD14 + and CD14 - cells using Miltenyic magnetic microbeads kits, respectively, according to the manufacturer's protocol. The resulting HLA-DR -CD14 + and HLA-DR -CD14 - cells were stored at -80°C until use. Flow cytometric assay:HLA-DR -CD14 + and HLA-DR -CD14 - cells were stained with both anti-human CD274 (PD-L1) FITC and human CD279 (PD-1) PE (BD Biosceinces, Inc.), together with anti-human CD14 APC or anti-human CD33 APC (BD Biosceinces, Inc.), respectively. Flow cytometric assessment was done using the BD Accuri C6 flow cytometer. While HLA-DR -CD14 +Monocytic MDCS cells were gated and assayed for surface expression of PD-1 (CD274) and PDL-1 (CD279), G-MDSC (granulocytic MDSC), and M-NDSC (Monocytic MDSC) were assayed as HLA-DR -CD14 - , CD33 + and HLA-DR -CD14 +, respectively. These MDSCs were then assayed for surface expression of PD-1 (CD274) and PDL-1 (CD279). The flow data were analyzed using FlowJo V8 (Flowjo, LLC), and the mean fluorescent intensity (MFI) was calculated. Results. PD-L1 on the m-MDSCs was significantly elevated in patients with MPN (grouping patients with ET, PV, and MF) and MF than controls. PD-1 on the M-MDSCs was not different between ET, PV, MF, or MPN compared with normal controls. Compared to controls, PD-L1 on the G-MDSC was significantly elevated in patients when ET, PV, and MF were grouped as MPN. PD-1 on the G-MDSC were not different between ET, PV, MF, or MPN and controls. Conclusion. Ph(-) MPN was found to have significantly elevated PD-L1 on the M-MDSCs and G-MDSCs, but PD-1 levels were not significantly elevated. Further studies to employ drugs, such as a combination of IMiDs (e.g., lenalidomide) and anti-MDSC drugs in combination with ICI in vitro and clinical trials, may be warranted. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.
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Giallongo, Cesarina, Nunziatina L. Parrinello, Daniele Tibullo, Piera La Cava, Alessandra Romano, Annalisa Chiarenza, Fabio Stagno, et al. "Monocytic Myeloid Derived Suppressor CELLS (M-MDSC) As Prognostic Factor in Chronic Myeloid Leukemia Patients Treated with Dasatinib." Blood 126, no. 23 (December 3, 2015): 2767. http://dx.doi.org/10.1182/blood.v126.23.2767.2767.
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Abstract INTRODUCTION. Myeloid suppressor cells are a heterogeneous group of myeloid cells that are increased in most cancer patients. Recently, we and another group demonstrated that MDSC play an important role of immune escape in chronic myeloid leukemia (CML) patients inducing T cell tolerance. The aim of this study was to investigate the effect of the tyrosine kinase inhibitors (TKI) therapy on MDSC and possible correlation with clinical response. METHODS. MDSCs were analyzed in peripheral blood of 20 healthy donors (HD) and 30 CML patients at diagnosis. MDSCs were also measured during TKI treatment (18 patients treated with imatinib and 10 patients with dasatinib). Granulocytic MDSCs (G-MDSCs) were identified as CD11b+CD33+CD14-HLADR- cells, while the monocytic MDSCs (M-MDSCs) as CD14+HLADR by cytofluorimetric analysis. Immuno-suppressive activity was tested through incubation of MDSCs with autologous CFSE-labeled T cells and stimulation with phytohaemagglutinin (PHA). Controls included a positive T cell proliferation control (T cells plus PHA) and a negative one (T cells only). After three days, T cell proliferation was analyzed by flow cytometry. Exosomes were isolated from CML serum at diagnosis (n=5) by sequential ultracentrifugation. RESULTS. G-MDSCs and M-MDSCs percentages in CML patients were greater than HD (respectively 82.5±9.6% vs 56.2±5.4% and 33.6±19% vs 5.9±4%, p<0.0001). Both isolated subpopulations showed expression of BCR/ABL and were able to inhibit T cells proliferation in comparison to positive control (from 48±7.6% to 25±5% for G-MDSC, p=0.0057 and 16.7±0.6% for M-MDSC, p<0.0001). No suppressive effect was observed in co-cultures with G-MDSC and M-MDSC obtained from HD. In addition, M-MDSC percentage correlated with BCR-ABLABL transcript levels in patients at diagnosis (r=0.5816, p=0.0006). Evaluating the effect of TKI therapy on MDSC levels, we found that both imatinib (IM) and dasatinib (DAS) induced a significant reduction of G-MDSC percentage at 6 months (from 82.5±9.6% to 55±17.3% after IM and 48.7±13% after DAS, p<0.0001) and 12 months (61.2±9.7% after IM and 33.4±14% after DAS, p<0.0001) of treatment. The levels of M-MDSCs significantly decreased only after DAS therapy (from 33.6±19% to 6.8±12.6% at 6 months, p=0.014 and 11.4±12.3% at 12 months, p=0.008); while there was a mild reduction after IM treatment (22.2±24.5% and 22.3±21.7% respectively at 6 and 12 months) although a great variability was observed among patients. Subsequently, correlation of MDSC reduction and clinical response to TKI therapy was investigated. We found that in DAS, but not in IM treated patients, a correlation between percentage of Major Molecular Response (MMR) and number of persistent M-MDSCs was found.. In fact, a significant difference was recorded by comparing M-MDSC levels in the MMR group (n=6) versus no MMR (n=4) at 6 or 12 months (p=0.0034). In addition, to evaluate if leukemic cells are able to expand MDSC by releasing soluble factors or exosomes, we incubated monocytes obtained from HD with sera or exosomes from CML patients at diagnosis or healthy subjects. M-MDSCs percentage significantly increased only in conditions with CML serum ( 29±13%; p=0.0006) or exosomes (8 ±2,8%; p=0.01) while no effect was observed on G-MDSC percentage. CONCLUSION: Therapy with TKI reduces the percentage of MDSCs and levels of the monocytic subset correlates with MMR in patients treated with dasatinib, suggesting their importance in clinical investigation as prognostic factor. Moreover, our data suggest the possible development in CML patients of a circuit primed by tumor cells that, through the release of soluble factors and exosomes, are able to expand M-MDSCs, creating an immunotolerant environment that results in T cell anergy and facilitates tumor growth. Disclosures No relevant conflicts of interest to declare.
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Ornstein, Moshe Chaim, C. Marcela Diaz-Montero, Patricia A. Rayman, Paul Elson, Samuel Haywood, Jin Sub Kim, Paul G. Pavicic, et al. "Myeloid derived suppressor cells (MDSC) and inflammatory biomarkers in metastatic urothelial carcinoma (mUC)." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): 4548. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.4548.
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4548 Background: MDSC are potent immunosuppressive cells with prognostic implications in many solid tumors. We previously reported significant correlations between MDSC and clinicopathologic features in localized UC. We hypothesized that different MDSC populations may correlate with inflammatory biomarkers and clinicopathologic features in mUC. Methods: Peripheral blood samples were collected from 46 mUC pts. MDSCs were measured in fresh unfractionated whole blood (WB) and in peripheral blood mononuclear cells (PBMC). MDSCs were identified by flow cytometry in WB and defined as LinloCD33+/HLADR- [(T)otal MDSC]. MDSC subsets were defined as (G)ranulocytic (CD15+CD14-), (M)onocytic (CD15-CD14+), (I)mmature (CD15-CD14-), or CD11b+. MDSC populations were presented as % of live nucleated blood cells and as absolute numbers from WB. Spearman correlations (r) and Wilcoxon rank sum test were used to assess correlations between MDSC populations & clinicopathologic factors. Results: Of 46 pts:78% men, median age at diagnosis 69 (31-83), 33% never smokers, 76% pure UC, 76% bladder primary, 28% prior intravesical therapy, 35% prior neoadjuvant chemotherapy, 56% prior cystectomy, 83% overweight/obese. G-MDSC was the predominant subset in WB (43%) and PBMC (39%), although M-MDSC were almost equally predominant in PBMC (35%). There was a correlation between the WB and PBMC values of T-, I-, and M- MDSC (p≤0.05). Higher % WB I-MDSC correlated with lower blood neutrophil/lymphocyte ratio (NLR) (p = 0.009), while higher WB G-MDSC and %PBMC G-MDSC were associated with higher NLR (p = 0.03 and p = 0.02, respectively). Higher I-MDSC / G-MDSC ratio was associated with lower NLR (r = -0.35, p = .02) and with various clinicopathologic parameters. Conclusions: HigherI-MDSC / G-MDSC ratio correlates inversely with NLR, which is considered an inflammatory biomarker and had prognostic value in other studies. The mechanism of MDSC interaction with inflammatory response in mUC pts merits evaluation and is being investigated in a larger cohort of UC pts on chemotherapy or immunotherapy (with longer follow up).
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Morenkova, A. Yu, M. A. Tikhonova, T. V. Tyrinova, E. V. Batorov, A. E. Sizikov, O. A. Chumasova, A. E. Sulutian, A. A. Ostanin, and E. R. Chernykh. "Expansion of myeloid-derived suppressor cells in the peripheral blood of patients with ankylosing spondylitis." Medical Immunology (Russia) 23, no. 2 (May 3, 2021): 327–38. http://dx.doi.org/10.15789/1563-0625-eom-2143.
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Expansion of myeloid-derived suppressor cells (MDSCs) due to impaired differentiation of myeloid progenitor cells under conditions of inflammation was described in a number of autoimmune diseases, including rheumatoid arthritis, systemic lupus erythematosus, and type 1 diabetes mellitus. Studying the role of MDSCs in ankylosing spondylitis is an important issue, given that increased concentration of proinflammatory mediators in this pathology can also cause myelopoiesis disorders. The aim of present work was to study the quantitative content of MDSC subpopulations in patients with different clinical phenotypes and activity of AS. 37 patients, including 10 patients without peripheral skeletal lesions (axial form) and 27 patients with simultaneous lesions of spine and peripheral joints (peripheral form) were recruited into the study. The control group consisted of 32 age/sex-related healthy donors. Evaluation of granulocytic (LinHLA-DRCD33+CD66b+; G-MDSC), monocytic (CD14+HLA-DRlow/-; M-MDSC) and early-stage MDSCs (LinHLA-DRCD33+CD66b- ; E-MDSC) was performed using corresponding antibodies (BD Biosciences, USA) in the population of peripheral blood mononuclear cells by flow cytometry. In general, the AS patients were characterized by an increased relative and absolute amount of M-MDSC (p = 0.00002 and p = 0.00003, respectively) and G-MDSC (p = 0.0002 and p = 0.0006, respectively). Patient gender, age, and HLA-B27 expression did not significantly affect the content of these cells in peripheral blood. An increase in the median values of M-MDSC was detected both in patients with axial (Ме 5.0 (3.2-6.3) versus 2.4 (1.7-3.5) %; p = 0.001) and peripheral form (Ме 5.0 (3.0-7.0) versus 2.4 (1.7-3.5) %; p = 0.0002) AS. At the same time, the G-MDSC expansion was observed only in patients with involvement of peripheral joints (Ме 0.16 (0.07-0.3) % versus 0.05 (0.04-0.09) %; p = 0.0001). The relative contents of E-MDSC, M-MDSC and G-MDSC in the axial form of AS was in direct correlation with the activity of the disease (R = 0.58, p = 0.02; R = 0.73, p = 0.08 and R = 0.65 p = 0.04, respectively). This relationship was not observed in peripheral form of AS. The data obtained suggest a potential involvement of MDSCs in pathogenesis and phenotypic heterogeneity of AS. Simultaneously, the revealed direct correlation between the MDSC contents and the disease activity suggests a decrease in suppressive activity and/or appearance of pro-inflammatory activity in MDSC, thus requiring further research in the field.
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Timganova, V. P., M. S. Bochkova, S. V. Uzhviyuk, K. Yu Shardina, S. A. Zamorina, and M. B. Rayev. "Generation of human myeloid suppressor cells in the in vitro experimental model." Russian Journal of Immunology 23, no. 2 (April 15, 2020): 157–62. http://dx.doi.org/10.46235/1028-7221-352-goh.
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Myeloid suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells that generally differentiate into macrophages, granulocytes, and dendritic cells. However, in pathology, these cells acquire a suppressor phenotype, blocking immune response. In particular, MDSC levels increase in many pathological conditions, including inflammation, sepsis, traumatic shock, autoimmune diseases, cancer, and pregnancy. Over the past 12 years, an interest in examining this cell population has been steadily increased [PUBMED: 2008 (65 articles); 2020 ( 650 entries)] that will expand our understanding of immune system functioning. In humans, MDSCs are characterized by HLA-DR-CD33+CD11b+ phenotype, in turn being subdivided into CD15+ or CD66+ granulocytic (G-MDSC), CD14+ monocytic (M-MDSC), and early (e-MDSC) MDSC bearing HLA-DR-CD11b+CD33+CD14-CD66b- phenotype. This work was aimed to develop an adequate experimental model allowing to evaluate cytokine-driven differentiation of human MDSCs from peripheral blood mononuclear cells in long-term in vitro culture system. For this, peripheral blood mononuclear cells were isolated from healthy donors induced to express MDSC phenotype with GM-CSF and IL-6 (40 or 20 ng/ml) cultured for 7, 14, 21 days. In several experiments, LPS (100 ng/ml) was added to the cultured cells 24 hours before immunophenotyping. The percentage of living Zombie Aquanegative cells in cultures (gated on cells according to FSC/SSC) ranged from 90.5-93.9%. No significant differences were observed between cultured cells. In our experimental conditions, the mean percentage of total MDSC subpopulation reached 2-2.3% of total living cells, exceeding that one by 9-10-fold found in freshly isolated mononuclear cells from healthy subjects. Based on the results of our experimental study, we found that induction of e-MDSC derived from human peripheral blood mononuclear cells requires two weeks of co-culture with 40 ng/ml IL-6 and 40 ng/ml GM-CSF. “Mature” MDSCs (M-MDSC + G-MDSC) yield was peaked in the following conditions: co-culture for 3 weeks with 20 ng/ml IL-6 and 20 ng/ml GM-CSF added with 100 ng/ml LPS 24 hours before completing protocol. Overall, further examining factors modulating MDSC differentiation will reveal conditions necessary for generating this suppressor cell subset potentially used in clinical practice.
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Haverkamp, Jessica, Amber Smith, Joseph Qualls, Liza Balouzian, Vincenzo Bronte, Joseph Opferman, and Peter Murray. "Monocytic lineage myeloid-derived suppressor cells are the principal suppressor population (48.11)." Journal of Immunology 188, no. 1_Supplement (May 1, 2012): 48.11. http://dx.doi.org/10.4049/jimmunol.188.supp.48.11.
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Abstract Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of immunosuppressive cells and are identified in mice as Gr-1+ (Ly6G/C) CD11b+ cells with the ability to inhibit T cell proliferation. However, the key functional immunosuppressive MDSC population remains controversial. Functional dissection of MDSCs is limited by population heterogeneity because Ly6C is expressed on mature and immature monocytic and granulocytic cells, each of which could potentially mediate immunosuppression. Here we describe genetic and chemical strategies allowing us to ablate the entire population of granulocytic or monocytic MDSCs specifically. Our data define the monocytic-macrophage MDSC population as the predominant suppressor population. Furthermore, our data have implications for the engineering of MDSCs as active suppressors for autoimmune diseases and targeted therapies aimed at selective ablation of monocytic MDSC in the treatment of cancer.
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Sprouse, Marc L., Thomas Welte, Debasish Boral, Haowen N. Liu, Wei Yin, Monika Vishnoi, Debalina Goswami-Sewell, et al. "PMN-MDSCs Enhance CTC Metastatic Properties through Reciprocal Interactions via ROS/Notch/Nodal Signaling." International Journal of Molecular Sciences 20, no. 8 (April 18, 2019): 1916. http://dx.doi.org/10.3390/ijms20081916.
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Intratumoral infiltration of myeloid-derived suppressor cells (MDSCs) is known to promote neoplastic growth by inhibiting the tumoricidal activity of T cells. However, direct interactions between patient-derived MDSCs and circulating tumors cells (CTCs) within the microenvironment of blood remain unexplored. Dissecting interplays between CTCs and circulatory MDSCs by heterotypic CTC/MDSC clustering is critical as a key mechanism to promote CTC survival and sustain the metastatic process. We characterized CTCs and polymorphonuclear-MDSCs (PMN-MDSCs) isolated in parallel from peripheral blood of metastatic melanoma and breast cancer patients by multi-parametric flow cytometry. Transplantation of both cell populations in the systemic circulation of mice revealed significantly enhanced dissemination and metastasis in mice co-injected with CTCs and PMN-MDSCs compared to mice injected with CTCs or MDSCs alone. Notably, CTC/PMN-MDSC clusters were detected in vitro and in vivo either in patients’ blood or by longitudinal monitoring of blood from animals. This was coupled with in vitro co-culturing of cell populations, demonstrating that CTCs formed physical clusters with PMN-MDSCs; and induced their pro-tumorigenic differentiation through paracrine Nodal signaling, augmenting the production of reactive oxygen species (ROS) by PMN-MDSCs. These findings were validated by detecting significantly higher Nodal and ROS levels in blood of cancer patients in the presence of naïve, heterotypic CTC/PMN-MDSC clusters. Augmented PMN-MDSC ROS upregulated Notch1 receptor expression in CTCs through the ROS-NRF2-ARE axis, thus priming CTCs to respond to ligand-mediated (Jagged1) Notch activation. Jagged1-expressing PMN-MDSCs contributed to enhanced Notch activation in CTCs by engagement of Notch1 receptor. The reciprocity of CTC/PMN-MDSC bi-directional paracrine interactions and signaling was functionally validated in inhibitor-based analyses, demonstrating that combined Nodal and ROS inhibition abrogated CTC/PMN-MDSC interactions and led to a reduction of CTC survival and proliferation. This study provides seminal evidence showing that PMN-MDSCs, additive to their immuno-suppressive roles, directly interact with CTCs and promote their dissemination and metastatic potency. Targeting CTC/PMN-MDSC heterotypic clusters and associated crosstalks can therefore represent a novel therapeutic avenue for limiting hematogenous spread of metastatic disease.
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Yang, Yingcui, Mingqing Zhang, Yongdan Zhang, Kebin Liu, and Chunwan Lu. "5-Fluorouracil Suppresses Colon Tumor through Activating the p53-Fas Pathway to Sensitize Myeloid-Derived Suppressor Cells to FasL+ Cytotoxic T Lymphocyte Cytotoxicity." Cancers 15, no. 5 (March 2, 2023): 1563. http://dx.doi.org/10.3390/cancers15051563.
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Myelosuppression is a major adverse effect of 5-fluorouracil (5-FU) chemotherapy. However, recent findings indicate that 5-FU selectively suppresses myeloid-derived suppressor cells (MDSCs), to enhance antitumor immunity in tumor-bearing mice. 5-FU-mediated myelosuppression may thus have a beneficial effect for cancer patients. The molecular mechanism underlying 5-FU’s suppression of MDSCs is currently unknown. We aimed at testing the hypothesis that 5-FU suppresses MDSCs through enhancing MDSC sensitivity to Fas-mediated apoptosis. We observed that, although FasL is highly expressed in T cells, Fas is weakly expressed in myeloid cells in human colon carcinoma, indicating that downregulation of Fas is a mechanism underlying myeloid cell survival and accumulation in human colon cancer. 5-FU treatment upregulated expression of both p53 and Fas, and knocking down p53 diminished 5-FU-induced Fas expression in MDSC-like cells, in vitro. 5-FU treatment also increased MDSC-like cell sensitivity to FasL-induced apoptosis in vitro. Furthermore, we determined that 5-FU therapy increased expression of Fas on MDSCs, suppressed MDSC accumulation, and increased CTL tumor infiltration in colon tumor-bearing mice. In human colorectal cancer patients, 5-FU chemotherapy decreased MDSC accumulation and increased CTL level. Our findings determine that 5-FU chemotherapy activates the p53-Fas pathway, to suppress MDSC accumulation, to increase CTL tumor infiltration.
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Ding, Zequn, and Yan Zhang. "Differentiation and Immunological Function of MDSC-Derived Dendritic Cells." Global Medical Genetics 09, no. 04 (December 2022): 290–99. http://dx.doi.org/10.1055/s-0042-1756659.
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AbstractDendritic cells (DCs) play a key role in initiating and regulating immune responses, and in addition to their roles in vivo, DCs are used as natural adjuvants for various tumor vaccines. In vitro, monocytes can be used to induce DCs, but in tumor patients, due to insufficient bone marrow hematopoiesis, extramedullary hematopoiesis and tumor-associated myeloid cells expand, and monocytes mainly exist in the form of myeloid-derived suppressor cells (MDSCs). The purpose of this experiment was to explore the differences in the differentiation and immune function of DCs induced by MDSCs in tumor patients. In a mouse model, we used normal mouse bone marrow cell-derived DCs as control cells, and in a tumor-bearing model, we induced MDSCs in the spleen to generate DCs (MDSC-DCs). Through flow cytometry, we found that the production of MDSC-DCs was significantly higher than that of control mice, and the secretion of interferon-γ of MDSC-DCs was significantly reduced. Through OVA antigen presentation experiments, we found that the antigen presentation ability of MDSC-DCs was significantly decreased. Through adoptive treatment of tumor-bearing mice cells, we found that the antitumor immune function of MDSC-DCs was significantly reduced. After that, we explored the mechanism of the decrease of immune function activity of MDSC-DCs. We determined that the surface markers of MDSC-DCs were changed by flow cytometry. Through flow sorting and RNA sequencing, we found that some pathways and key gene expression in MDSC-DCs were changed. In conclusion, this study found that the immune function of MDSC-DCs decreased and explored the mechanism of the decreased immune function activity.
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Kim, Il-Hwan. "Anti-HER2/Neu antibody therapy can reduce the immunosuppressive activity of MDSCs in breast tumor model." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): e14181-e14181. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.e14181.
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e14181 Background: Myeloid-derived suppressor cells (MDSCs) are a heterogeneous cell populations that play a critical role in tumor associated immune suppression. MDSCs consist of immature cells with myeloid lineage markers CD11b and Gr1 in mice and accumulate in large numbers in tumor bearing mice including HER2/neu+ breast cancers. This study was conducted to test whether anti-neu antibody treatment can affect on MDSC populations and immunosuppressive functions. Methods: Female BALB/c mice(5–6weeks of age) were used. The TUBO mammary carcinoma cell line was cloned from a spontaneous mammary tumor in a BALB Neu Tg mouse, as cell lines and reagents. Tumor-infiltrating lymphocyte (TIL) populations were evaluated by flow cytometry. The RT2 Profiler PCR array was used for cytokine expression analysis according to the manufacturer’s instructions. Results: Total number of MDSC in tumor and spleen were decreased within 3 days after anti-neu antibody treatment, but percentage of MDSC in tumor (day2) was reduced more quickly than percentage of MDSC in spleen (day3). The relative populations of MDSC in CD45.2+ cells were significantly decreased such as MO-MDSC. Immunosuppressive activity of MDSC was also reduced by anti-neu antibody treatment. MDSC reduced by anti-neu antibody was due to inhibition of the immunosuppressive factors Arg1 and IDO. In addition, combination therapy with 5-FU may enhance MDSC reduction. Conclusions: MDSC can be a potential therapeutic target in anti-neu antibody treated therapeutic model and the effect of anti-neu antibody could be further improved using other therapeutic treatment to target MDSC.
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Talmadge, James E., Phyllis Warkentin, Holly Briitton, Lynell W. Klassen, and Kathryn Cole. "Spanning tree progression analysis of density normalized events (SPADE) identification of novel myeloid derived suppressor cells (MDSC) subsets." Journal of Immunology 200, no. 1_Supplement (May 1, 2018): 46.14. http://dx.doi.org/10.4049/jimmunol.200.supp.46.14.
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Abstract MDSC’s are a heterogeneous population of myeloid cells at various differentiation stages. The human MDSC phenotypes, are controversial and subdivided into macrophage (M-), granulocytic (G-) and immature (i-) MDSC’s. Our studies used a single staining tube with antibodies to linage markers (CD3, CD19 and CD56), HLA-DR, CD11b, CD14, CD15, CD16, CD33, CD45, PD-L1 and LOX-1. Mobilized lymphoma patient apharesis (CA) products provided a product with a high frequency of MDSCs compared to normal donor blood samples (PB). SSCA and FSA identified lymphocytes, granulocytes and monocyte populations. A total population (CD45+), MDSCs (Lin-HLA-DR-CD11b+CD14+, Lin-HLA-DR-CD11b+CD14-CD33+ and Lin-HLA-DR−CD11b+ CD15+) and non MDSC myeloid populations (Lin-HLA-DR+CD14+, Lin-HLA-DR+CD33+ and Lin-HLA-DR+ CD15+Lin-HLA-DR-11b-) were exported from FlowJo for Spade analysis. This identified 11 nodes with 4 MDSC sub-populations. Impressively, cells from the non-MDSC populations, including monocytes and granulocytes did not occur within these nodes. SPADE identified an M-MDSC, G-MDSC and two iMDSC subsets with an increased frequency in the CA samples. Increased expression of LOX-1 and CD16 occurred in CA MDSCs vs. PB. Intracellular staining for expression of NOS-2 and Arg-1 were consistent with the M and G-MDSC subsets. Node 7 mainly expressed M-MDSC’s with a low frequency of CD15 dull G-MDSC’s. The cell frequency for G-MDSC’s in node 7 was 1,334 for CA and 0 for PB with M-MDSC’s 1,079 and 43 respectively. Node 8 had a frequency (3,319) of G-MDSC’s for CA and 2,286 for PB with M-MDSC’s 188 and 15 respectively. In summary SPADE analysis can be used to cleanly identify MDSCs from monocytes and granulocytes and provide insight into novel MDSC subsets.
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Damle, Sheela, Rebecca Martin, Sheinei Saleem, Lauren Folgosa, Hannah Zellner, Kim Nguyen, John Ryan, Harry Bear, Anne Marie Irani, and Daniel Conrad. "Mast cells and mast cell-derived IL-13 play an important role in MDSC activation, migration, and accumulation. (TUM4P.925)." Journal of Immunology 192, no. 1_Supplement (May 1, 2014): 138.26. http://dx.doi.org/10.4049/jimmunol.192.supp.138.26.
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Abstract Until recently, the interaction between mast cells (MCs) and CD11b+Gr-1+ myeloid derived suppressor cells (MDSCs) was limited to recruitment of MDSCs to the tumor site. However, we report that MCs are also needed for the activity of MDSCs. Adoptive transfer (AT) of MDSCs failed to promote B16 melanoma colonization in MC deficient mice. MDSCs in these mice also failed to localize to the liver and stayed mainly in peripheral blood. MC sufficient mice accumulated MDSCs in the liver and retained significantly lower levels of MDSCs in circulation after AT. Recently, Ma et al. (Cancer Res. 2013 Jul 1; 73(13);3927-37.) has shown that MC derived IL-13 has been show to promote the growth of pancreatic ductal carcinoma. Given this, we investigated the role that IL-13 plays in the MDSC/MC interaction. Our data shows that IL-13 KO mice crossed to ADAM10Tg mice, which carry a mutation resulting in the over-accumulation of MDSCs, have significantly decreased MDSC accumulation in the naïve state, especially evident in the granulocytic subset. In a model of natural MDSC accumulation (Lewis Lung Carcinoma, i.v.), IL-13 KO mice had reduced tumor colonization to the lungs. They also had reduced MDSC accumulation in the liver and spleen, but increased number in circulation. Taken together, our data indicates that MCs and IL-13, an important MC-derived cytokine, play an important role in MDSC migration and accumulation and represent important drug targets for the control of MDSCs in tumor.
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Ornstein, Moshe Chaim, C. Marcela Diaz-Montero, Patricia A. Rayman, Paul Elson, Samuel Haywood, Jin Sub Kim, Paul G. Pavicic, et al. "Assessment of blood and tissue myeloid derived suppressor cells (MDSC), clinicopathologic factors, and treatment response in urothelial carcinoma (UC) patients (pts) undergoing surgery." Journal of Clinical Oncology 35, no. 6_suppl (February 20, 2017): 362. http://dx.doi.org/10.1200/jco.2017.35.6_suppl.362.
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362 Background: MDSC are heterogeneous immunosuppressive cells with potential predictive/prognostic role in cancer. The association between MDSC, clinicopathologic factors and pathologic response in pts with UC merits evaluation. Methods: Peripheral blood and/or tissue was collected from 120 pts. MDSC were measured in fresh unfractionated whole blood (WB), in peripheral blood mononuclear cells (PBMC) and fresh tumor tissue. MDSCs were identified by flow cytometry in WB and defined as LinloCD33+/HLADR- ((T)otal MDSC). MDSC subsets were defined as LinloCD33+/HLADR- and (G)ranulocytic (CD15+CD14-), (M)onocytic (CD15-CD14+), (I)mmature (CD15-CD14-, CD11b+ ). MDSC populations were presented as % of live nucleated blood cells and as absolute numbers from WB. Spearman correlations (r) and Wilcoxon rank sum test were used to assess correlations between MDSC populations, clinicopathologic factors and pT0N0%. Results: Of 120 pts, 82 were non-metastatic: 58 had only blood, 23 had blood & tissue, 1 had only tissue available for analysis. Of these 82 non-metastatic pts, 70 were men, median age 68; 81 pts had primary UC histology, 1 small cell cancer, 24 had mixed UC histology; 24 had prior intravesical therapy, 34 had neoadjuvant therapy (79% cisplatin-based, 21% unknown), 4 pts had post-op recurrence. At cystectomy: 15/82 pT0, 22/82 pT3/4; 37/82 CIS; 8/78 pN+. Significant associations were seen between MDSC blood levels and mixed histology, CIS, pN+, and lower pT0N0% (Table). Tumor M-MDSCs were associated with pN+ (p=0.05). There was significant correlation between tumor and WB % M-MDSC (r=0.55, p=0.007), and tumor and WB % G-MDSC (r=0.46, p=0.03). Conclusions: Blood MDSC levels correlate with several clinicopathologic factors and may predict pathological complete response (pT0N0). Assessment of association between MDSC levels, outcome and immunotherapy response is ongoing including in metastatic pts. [Table: see text]
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Au, Qingyan, Jun Fang, Anna Juncker-Jensen, Judy Kuo, Eric Leones, Flora Sahafi, RaghavKrishna Padmanabhan, Nicholas Hoe, and Josette William. "Characterization of Myeloid-Derived Suppressor Cells and Tumor Associated Macrophages Using MultiOmyxTM Hyperplexed Immunofluorescence Assay in Hodgkin Lymphoma." Blood 132, Supplement 1 (November 29, 2018): 4135. http://dx.doi.org/10.1182/blood-2018-99-115434.
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Abstract Tumor microenvironment (TME) consists of heterogeneous subsets of myeloid cells and plays a crucial role in promoting cancer development and metastasis. Tumor associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) all contribute to an immunologically permissive microenvironment for cancer cells. On basis of the expression of surface markers, MDSC can be further subdivided into granulocytic MDSC (G-MDSC, polymorphonuclear MDSC) and monocytic MDSC (M-MDSC). In solid tumors, these different myeloid cell populations are well characterized and extensively studied. However, in hematological malignancies the role of myeloid cell subsets has been less studied. A recent study showed increase in MDSC in the bone marrow (BM) at time of diagnosis in acute myeloid leukemia (AML) patients (Sun H. et al. Int J Hematol. 2015). Significantly higher numbers of G-MDSC and M-MDSC were present at diagnosis in classic Hodgkin lymphoma (cHL) (Romano A. et al. Br J Haematol. 2015). The accumulation of TAMs was also reported to be associated with poor prognosis in cHL (Steidl C. et al. N Engl J Med. 2010). Collectively, these results indicate that the tumor-resident myeloid cells play an important clinical role, thus highlighting the need for monitoring and deeper characterization of various myeloid subsets in hematological malignancies, especially in the tumor FFPE sections. Herein, we report an analysis of MDSCs and 'protumoral' M2 macrophages using MultiOmyx hyperplexed immunofluorescence (IF) assay in 9 clinical samples diagnosed with HL. MultiOmyx is a proprietary multi 'omic' technology that enables detection and visualization of up to 60 biomarkers on a single 4µM FFPE slide (Gerdes MJ. et al. PNAS 2013). The HL FFPE sections were stained with a 13-marker panel including Arginase 1, CD11b, CD14, CD15, CD16, CD33, CD68, CD163, HLA-DR, CD3, CD4, CD8 and FOXP3. We observed that both M-MDSC (Fig 1A, characterized as CD11b+CD14+CD15-CD33+HLA-DR-) and G-MDSC (Fig 1B, identified as CD11b+CD14-CD15+CD33+HLA-DR-) accumulated within the TME in all 9 HL samples, with higher frequency of G-MDSCs over M-MDSCs. Arg1 expression was detected exclusively in G-MDSC population (Fig 1C). The data also revealed an abundant M2 macrophages (Fig 1D, characterized as CD68+CD163+) present in all HL samples. The detection of both MDSCs and M2 macrophages in HL samples supports the hypothesis that these cells contribute to the establishment of an immunosuppressive TME. Using the MultiOmyx proprietary algorithm, which takes into account the staining patterns, we will next quantify the counts and density of different tumor-resident myeloid subsets and measure the spatial distance between each subset of tumor-resident myeloid cells to the neoplastic Reed-Sternberg cells. Correlation study will also be performed to determine if significant correlations exist between MDSCs and TAMs and how these immunosuppressive myeloid cells are related to the Regulatory T cells (CD3+CD4+FOXP3+) in HL samples. In addition to HL samples, the same 13-plexed panel will be utilized to characterize the myeloid cell population from AML patients. TAMs and MDSCs are emerging as potential biomarkers for diagnosis and prognosis of cancer as well as therapeutic targets. The comprehensive myeloid cells phenotyping offered by MultiOmyx 13-plexed panel has the potential to monitor the changes of immunosuppressive myeloid cells in response to immune modulating drugs such as MDSC-targeting drugs (e.g. PDE-5 inhibitors, COX-2 inhibitors), TAM-targeting agents (e.g. anti-CSF1R) and combined therapy in treatment of lymphoma and leukemia. Disclosures No relevant conflicts of interest to declare.
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Van Valckenborgh, Els, Jo Van Ginderachter, Kiavash Movahedi, Eline Menu, and Karin Vanderkerken. "Myeloid-Derived Suppressor Cells in Multiple Myeloma." Blood 114, no. 22 (November 20, 2009): 2794. http://dx.doi.org/10.1182/blood.v114.22.2794.2794.
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Abstract Abstract 2794 Poster Board II-770 Myeloid-derived suppressor cells (MDSCs) are a heterogeneous mix of myeloid cells in different maturation stages generated in the bone marrow. The role of MDSCs in cancer is to suppress T-cell responses, thereby likely regulating tumor progression. In mice, MDSCs are identified by the expression of the surface markers CD11b and Gr-1. Recently, Ly6G+ granulocytic (PMN-MDSC) and Ly6G− monocytic (MO-MDSC) subsets could be distinguished (Movahedi et al. Blood 2008, 111:4233-44). In multiple myeloma patients, the immune function is impaired and this is caused by an immunologically hostile microenvironment and cellular defects, such as decreased numbers of immune cells, and DC or T-cell dysfunction. However, the role of MDSCs in immune suppression in multiple myeloma is not yet described. In this study, we investigated the immunosuppressive activity and mechanism of MDSC subsets in the syngeneic and immunocompetent 5TMM mouse model (5T2 and 5T33 models). In first instance, CD11b+Ly6G− and CD11b+Ly6G+ lineage-committed myeloid MDSC subsets were detected in 5TMM-diseased bone marrow by flow cytometry. These subsets were purified via MACS from the bone marrow of naïve and 5TMM tumor-bearing mice, and analyzed for T-cell suppressive activity. Hereto, CD8+ TCR-transgenic OT-1 splenocytes were stimulated with ovalbumin protein in the presence of purified MDSC subsets, after which T-cell proliferation was measured via 3H-thymidine incorporation. Both MDSC subsets from 5TMM bone marrow were able to suppress antigen-specific T-cell responses at a higher level compared to purified MDSC subsets from normal bone marrow. On average, Ly6G− MDSCs were more suppressive than Ly6G+ MDSCs. The 5T2MM model has a tumor take of approximately 12 weeks. Three weeks after intravenous inoculation of the tumor cells, the suppressive effect of the myeloid subsets was already observed (while the plasmacytosis in the BM was very low and no detectable serum M spike was observed), indicating that T-cell suppression is an early event in MM development. To unravel the suppressive mechanism of the MDSC subsets, inhibitors were used in ovalbumin-stimulated cocultures. Ly6G− MDSC-mediated suppression was partially reversed by the iNOS inhibitor L-NMMA and the COX-2 inhibitor sc-791, both of which lower the NO concentration in culture. In contrast, superoxide dismutase and especially catalase enhance NO concentrations, resulting in enhanced T-cell suppression. None of these inhibitors had any impact on the Ly6G+ MDSC-mediated suppression. In conclusion, these data reveal the presence of MDSCs as a novel immune suppressive strategy employed by multiple myeloma cells in the bone marrow, already occurring early in the disease process. Disclosures: No relevant conflicts of interest to declare.
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Tchao, Jason, Jong Jin Kim, Bo Lin, Guy Salama, Cecilia W. Lo, Lei Yang, and Kimimasa Tobita. "Engineered Human Muscle Tissue from Skeletal Muscle Derived Stem Cells and Induced Pluripotent Stem Cell Derived Cardiac Cells." International Journal of Tissue Engineering 2013 (December 5, 2013): 1–15. http://dx.doi.org/10.1155/2013/198762.
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During development, cardiac and skeletal muscle share major transcription factors and sarcomere proteins which were generally regarded as specific to either cardiac or skeletal muscle but not both in terminally differentiated adult cardiac or skeletal muscle. Here, we investigated whether artificial muscle constructed from human skeletal muscle derived stem cells (MDSCs) recapitulates developmental similarities between cardiac and skeletal muscle. We constructed 3-dimensional collagen-based engineered muscle tissue (EMT) using MDSCs (MDSC-EMT) and compared the biochemical and contractile properties with EMT using induced pluripotent stem (iPS) cell-derived cardiac cells (iPS-EMT). Both MDSC-EMT and iPS-EMT expressed cardiac specific troponins, fast skeletal muscle myosin heavy chain, and connexin-43 mimicking developing cardiac or skeletal muscle. At the transcriptional level, MDSC-EMT and iPS-EMT upregulated both cardiac and skeletal muscle-specific genes and expressed Nkx2.5 and Myo-D proteins. MDSC-EMT displayed intracellular calcium ion transients and responses to isoproterenol. Contractile force measurements of MDSC-EMT demonstrated functional properties of immature cardiac and skeletal muscle in both tissues. Results suggest that the EMT from MDSCs mimics developing cardiac and skeletal muscle and can serve as a useful in vitro functioning striated muscle model for investigation of stem cell differentiation and therapeutic options of MDSCs for cardiac repair.
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Corzo, Cesar A., Thomas Condamine, Lily Lu, Matthew J. Cotter, Je-In Youn, Pingyan Cheng, Hyun-Il Cho, et al. "HIF-1α regulates function and differentiation of myeloid-derived suppressor cells in the tumor microenvironment." Journal of Experimental Medicine 207, no. 11 (September 27, 2010): 2439–53. http://dx.doi.org/10.1084/jem.20100587.
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Myeloid-derived suppressor cells (MDSCs) are a major component of the immune-suppressive network described in cancer and many other pathological conditions. We demonstrate that although MDSCs from peripheral lymphoid organs and the tumor site share similar phenotype and morphology, these cells display profound functional differences. MDSC from peripheral lymphoid organs suppressed antigen-specific CD8+ T cells but failed to inhibit nonspecific T cell function. In sharp contrast, tumor MDSC suppressed both antigen-specific and nonspecific T cell activity. The tumor microenvironment caused rapid and dramatic up-regulation of arginase I and inducible nitric oxide synthase in MDSC, which was accompanied by down-regulation of nicotinamide adenine dinucleotide phosphate–oxidase and reactive oxygen species in these cells. In contrast to MDSC from the spleen, MDSC from the tumor site rapidly differentiated into macrophages. Exposure of spleen MDSC to hypoxia resulted in the conversion of these cells to nonspecific suppressors and their preferential differentiation to macrophages. Hypoxia-inducible factor (HIF) 1α was found to be primarily responsible for the observed effects of the tumor microenvironment on MDSC differentiation and function. Thus, hypoxia via HIF-1α dramatically alters the function of MDSC in the tumor microenvironment and redirects their differentiation toward tumor-associated macrophages, hence providing a mechanistic link between different myeloid suppressive cells in the tumor microenvironment.
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Miska, Jason, Catalina Lee Chang, Aida Rashidi, Yu Han, Aurora Lopez-Rosas, and Maciej S. Lesniak. "IMMU-43. POLYAMINE METABOLISM REGULATES MYELOID IMMUNE SUPPRESSION IN GLIOBLASTOMA." Neuro-Oncology 21, Supplement_6 (November 2019): vi128. http://dx.doi.org/10.1093/neuonc/noz175.535.
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Abstract Tumor-associated myeloid cells, which consist of tumor associated macrophages and myeloid-derived suppressor cells (MDSCs), make up a majority of cellular infiltrates in glioma. Glioma infiltrating MDSCs highly express arginase-1 (Arg-1), a catabolic enzyme thought to deplete arginine from the tumor microenvironment. Despite being a well-known marker of immunosuppressive cells, the metabolic reasons for this choice are not clear. Examination of MDSC phenotype in murine glioma models using: RNA-seq, bulk metabolomics, and Carbon-13 arginine flux revealed that two separate pathways of arginine catabolism converge on the generation of ornithine. Ornithine is the prerequisite substrate for the de-novo generation of polyamines, a group of nitrogen-rich metabolites with foundational importance to all mammalian, bacterial, and plant biology. Importantly, we found that the rate-limiting step of polyamine generation, ornithine decarboxylase 1 (ODC1), is dramatically upregulated by glioma infiltrating MDSCs, suggesting de-novo polyamine generation is important for MDSC function. Treatment with a specific inhibitor of de-novo polyamine synthesis, difluoromethylornithine (DMFO), inhibited the immunosuppressive function of in-vitro generated glioma associated MDSCs. However, DFMO only exerted effects before differentiation, as DFMO treatment post-generation did not change their suppressive functions. This suggests that the generation of the polyamine pool is critical to immune suppression by MDSCs. Interestingly the expression of the rate limiting step of polyamine degradation (SAT1) is inversely correlated with (ODC1) during MDSC differentiation, suggesting that utilization of this polyamine pool may be required for the suppressive functions of these cells. Inhibition of SAT1 after MDSC generation blunted MDSC mediated T-cell suppression. The results of this study show that the role of arginine metabolism in tumor infiltrating MDSCs is to generate pools of polyamines which maintain MDSC function in glioma. Therapeutic targeting of this pathway may be a novel and powerful tool to combat immunosuppression in glioma.
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Li, Xing, Xiang-yuan Wu, Nan Jiang, Yan-Fang Xing, Jie Chen, and Qu Lin. "Endoplasmic reticulum stress induced Lox-1+ CD15+ polymorphonuclear myeloid-derived suppressor cells in hepatocellular carcinoma and associated with poor prognsis." Journal of Clinical Oncology 36, no. 5_suppl (February 10, 2018): 38. http://dx.doi.org/10.1200/jco.2018.36.5_suppl.38.
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38 Background: A recent study indicated that Lectin-type oxidized LDL receptor-1 (LOX-1) was a distinct surface marker for human polymorphonuclears myeloid-derived suppressor cells (PMN-MDSC). The present study was aimed to investigate the existence LOX-1 PMN-MDSC in hepatocellular carcinoma (HCC) patients, the latent mechanism and their association with clinical parameters. Methods: 30 HCC patients and 30 health control were included. LOX-1+CD15+ PMN-MDSCs were investigated. Results: LOX-1+CD15+ PMN-MDSC were significantly elevated in both WB and PBMC of HCC patients compared with healthy control. LOX-1+CD15+ PMN-MDSC were more abundant in PBMC than WB. Addition of PMN-MDSCs resulted in significantly reduced proliferation and IFN-γ production of T cells with a dosage dependent manner. LOX-1-CD15+ PMNs present no suppressive function. The suppression on T cell proliferation and IFN-γ production was reversed by ROS inhibitor and Arginase inhibitor. ROS level of LOX-1+CD15+ PMN by DCFDA were higher in LOX-1+CD15+ PMN-MDSCs than LOX-1-CD15+ PMNs, as well as the mRNA levels of the NADPH oxidase NOX2. Meanwhile, the expression of arginase I and activity of arginase were also significantly raised in LOX-1+CD15+ PMN-MDSCs. LOX-1+CD15+ PMN-MDSCs displayed significantly higher expression of spliced X-box–binding protein 1 (sXBP1), ATF3 and CCAAT/enhancer binding protein (CHOP) were higher. For HCC patients, LOX-1+CD15+ PMN-MDSCs in WB were positively related to Cancer of the Liver Italian Program (CLIP) score. Conclusions: LOX-1+CD15+ PMN-MDSC were elevated in HCC patients and suppressed T cell proliferation through ROS/Arg I pathway with ER stress as a potential feature. LOX-1+CD15+ PMN-MDSC presented positive association with the prognosis of HCC patients.
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Green, Kathy A., and William R. Green. "5-Fluorouracil depletion of Myeloid Derived Suppressor Cells in mice infected with LP-BM5 retrovirus." Journal of Immunology 200, no. 1_Supplement (May 1, 2018): 182.24. http://dx.doi.org/10.4049/jimmunol.200.supp.182.24.
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Abstract Tumor associated MDSC inhibit tumor-directed T-cell responses. We have shown the induction of monocytic MDSCs (M-MDSC) during infection of B6 mice by LP-BM5 immunodeficiency inducing retrovirus. These M-MDSCs suppressed proliferation and function of T cells, ~100% via iNOS/NO; and that of B cells, ~50% via iNOS/NO along with the negative checkpoint regulator VISTA, NOS, ROS, and other soluble mediators. Because of overlapping cell-surface phenotypes, our attempts to selectively deplete M-MDSCs in vivo have been challenging. However, 5-Fluorouracil (5-FU), a pyrimidine analog widely used in tumor chemotherapy, has recently been reported to selectively eliminate MDSCs by apoptosis (Biomed. J. 2015:38:111–116). Here, we treated LP-BM5 infected mice with an extended course of 5-FU: at 6–7 weeks post infection achieving ~50% depletion of splenic M-MDSCs, and spleen cells from depleted mice exhibited greatly decreased suppression in ex vivo assays. LP-BM5 infected mice with this level of M-MDSC depletion, had significantly less disease, including: splenomegaly and immunodeficiency – i.e. impaired B and T-cell ex vivo polyclonal responses. Also, regarding other disease parameters, the loss of LP-BM5 induced splenic: CD4 Thy1.2 and B-cell CD23 expression was greatly reduced in M-MDSC depleted mice. As compared to sham treated mice, via flow cytometry, the splenic CD8+ T cell subset from LP-BM5 infected/M-MDSC depleted mice was greatly increased in cell number and MFI. Future directions include extending these initial experiments to further characterize the effects on B and T-cells resulting from in-vivo 5-FU-mediated M-MDSC depletion during LP-BM5 retrovirus-induced immunodeficiency.
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Guha, Prajna, Jillian Gardell, Mikayla Lopes, N. Joseph Espat, and Steven C. Katz. "Liver-specific programming of myeloid cells promotes intrahepatic immunosuppression." Journal of Immunology 200, no. 1_Supplement (May 1, 2018): 46.13. http://dx.doi.org/10.4049/jimmunol.200.supp.46.13.
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Abstract Liver is a tolerogenic organ and has variety of immune cells resulting in a profoundly immunosuppressive space. We recently reported that GM-CSF/JAK2/STAT3 axis drives liver myeloid suppressor cell (L-MDSC) proliferation and STAT3 inhibition causes activation of apoptosis signaling via Bax up-regulation. Herein, we explore liver specific programming events that promote L-MDSC suppressive conditioning. Bone marrow derived MDSC (BM-MDSC) were expanded in CD45.1+ mice in response to intraperitoneal MC38 tumors. CD45.1+ BM-MDSC were adoptively transferred into CD45.2+ recipient mice via tail vein (TV) or portal vein (PV). CD11b+ cells were harvested 48 hrs later from recipient liver and lungs. Liver from PV and lung from TV CD45.1+ MDSC recipients were compared. There was increased expansion of CD45.1+ MDSC (CD11b+Gr1+) in PV-liver as compared to TV-lung group (Liver-PV 45±3% vs. Lung-TV 15±2% vs. Tumor 43±3, p<0.001, n=5) with increased numbers of the more immunosuppressive monocytic MDSC (M-MDSC) subtype in CD45.1+ transferred cells in liver as compared to lung (Liver-PV 61±4%, Lung-TV 40±3%, Tumor 58±3 p<0.005, n=5). Enhanced pSTAT3 expression (mediator of MDSC expansion) in CD45.1+CD11b+Gr1+ cells in liver was observed as compared to lung (pSTAT3: Liver-PV 54±4, Lung-TV 30±5, p<0.05 n=5). Quantitative PCR of MDSCs isolated from Liver-PV showed significantly decreased levels (8.5 fold, p<0.05, n=4) of pro-apoptotic Bax protein as compared to Lung-TV indicating MDSC apoptosis resistance following conditioning in the liver. These data indicate that L-MDSCs are directed towards suppressive programming and blocking STAT3 may have clinical application for enhancing the efficacy of immunotherapy for liver tumors.
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Saleem, Sheinei, Rebecca Martin, Harry Bear, and Daniel Conrad. "Mast cell derived histamine promotes the activity of monocytic myeloid derived suppressor cells (P2065)." Journal of Immunology 190, no. 1_Supplement (May 1, 2013): 53.33. http://dx.doi.org/10.4049/jimmunol.190.supp.53.33.
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Abstract Until recently, the interaction between mast cells (MCs) and CD11b+Gr-1+ myeloid derived suppressor cells (MDSCs) was limited to recruitment of MDSCs to the tumor site. However, we report that MCs are also needed for the activity of MDSCs. MDSCs failed to promote B16 melanoma metastasis in MC deficient mice. This was dependent on monocytic Ly6C+ MDSCs while granulocytic Ly6G+ had no effect. In vitro studies showed increased Th2 cytokine production by both cells. Given these observations and literature indicating histamine as a promoter of tumor expansion, myeloid cell proliferation, and Th2 skewed immunity; we investigated histamine in the MC/MDSC interaction. MDSCs were shown to express histamine receptor 1 (HR1). Furthermore, histamine enhanced MDSC survival and preferentially expanded monocytic LY6C+ MDSCs. This was abrogated with HR1 antagonization. Additionally, histamine upregulated Arg1 and iNOS enzyme expression, both of which are utilized by MDSCs to inhibit T cell activity. This was further supported by the finding that in the presence of MCs, MDSCs were more effective at inhibiting T cell proliferation. Taken together, our data indicates that beyond recruitment, MCs regulate MDSC activity at the tumor site via histamine release. These findings have important implications for the use of anti-histamines in cancer patients being simultaneously treated for allergies. Oncologists should consider this new MC/MDSC interaction when determining therapeutic interventions.
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Lim, Hui Xuan, Tae Sung Kim, and Chit Laa Poh. "Understanding the Differentiation, Expansion, Recruitment and Suppressive Activities of Myeloid-Derived Suppressor Cells in Cancers." International Journal of Molecular Sciences 21, no. 10 (May 20, 2020): 3599. http://dx.doi.org/10.3390/ijms21103599.
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There has been a great interest in myeloid-derived suppressor cells (MDSCs) due to their biological functions in tumor-mediated immune escape by suppressing antitumor immune responses. These cells arise from altered myelopoiesis in response to the tumor-derived factors. The most recognized function of MDSCs is suppressing anti-tumor immune responses by impairing T cell functions, and these cells are the most important players in cancer dissemination and metastasis. Therefore, understanding the factors and the mechanism of MDSC differentiation, expansion, and recruitment into the tumor microenvironment can lead to its control. However, most of the studies only defined MDSCs with no further characterization of granulocytic and monocytic subsets. In this review, we discuss the mechanisms by which specific MDSC subsets contribute to cancers. A better understanding of MDSC subset development and the specific molecular mechanism is needed to identify treatment targets. The understanding of the specific molecular mechanisms responsible for MDSC accumulation would enable more precise therapeutic targeting of these cells.
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Alban, Tyler, Defne Bayik, Balint Otvos, Matthew Grabowski, Manmeet Ahluwalia, Richard Bucala, Michael Vogelbaum, and Justin Lathia. "IMMU-28. TARGETING IMMUNOSUPPRESSIVE MYELOID DERIVED SUPPRESSOR CELLS VIA MIF/CD74 SIGNALING AXIS TO ATTENUATE GBM GROWTH." Neuro-Oncology 21, Supplement_6 (November 2019): vi125. http://dx.doi.org/10.1093/neuonc/noz175.521.
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Abstract The immunosuppressive microenvironment in glioblastoma (GBM) enables persistent tumor growth and evasion from tumoricidal immune cell recognition. Despite a large accumulation of immune cells in the GBM microenvironment, tumor growth continues, and evidence for potent immunosuppression via myeloid derived suppressor cells (MDSCs) is now emerging. In agreement with these observations, we have recently established that increased MDSCs over time correlates with poor prognosis in GBM, making these cells of interest for therapeutic targeting. In seeking to reduce MDSCs in GBM, we previously identified the cytokine macrophage migration inhibitory factor (MIF) as a possible activator of MDSC function in GBM. Here, using a novel in vitro co-culture system to reproducibly and rapidly create GBM-educated MDSCs, we observed that MIF was essential in the generation of MDSCs and that MDSCs generated via this approach express a repertoire of MIF receptors. CD74 was the primary MIF receptor in monocytic MDSCs (M-MDSC), which penetrate the tumor microenvironment in preclinical models and patient samples. A screen of MIF/CD74 interaction inhibitors revealed that MN-166, a clinically relevant blood brain barrier penetrant drug, which is currently fast tracked for FDA approval, reduced MDSC generation and function in vitro. This effect was specific to M-MDSC subsets expressing CD74, and appeared as reduced downstream pERK signaling and MCP-1 secretion. In vivo, MN-166 was able reduce tumor-infiltrating MDSCs, while conferring a significant increase in survival in the syngeneic glioma model GL261. These data provide proof of concept that M-MDSCs can be targeted in the tumor microenvironment via MN-166 to reduce tumor growth and provide a rationale for future clinical assessment of MN-166 to reduce M-MDSCs in the tumor microenvironment. Ongoing studies are assessing the effects of MDSC inhibition in combination with immune activating approaches, in order to inhibit immune suppression while simultaneously activating the immune system.
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Hirsch, Aspen L., Cassandra L. Brenner, Alex B. Costa, James M. Haughian, Nicholas A. Pullen, and Reid Hayward. "Voluntary physical exercise decreases MDSC (myeloid derived suppressor cell) populations in the spleen and circulation in a rat model of mammary adenocarcinoma." Journal of Immunology 200, no. 1_Supplement (May 1, 2018): 56.10. http://dx.doi.org/10.4049/jimmunol.200.supp.56.10.
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Abstract Myeloid derived suppressor cells (MDSCs) are a heterogenous population of myeloid progenitor cells that suppress T cells and other potentially anti-cancer immune cells. MDSC presence in cancer patients can diminish immunotherapy response and worsen treatment outcomes. Here we examine a low-risk, low-cost approach to MDSC modulation by examining the impact of voluntary wheel-running exercise on MDSC populations in a Fisher-344 rat, MATBIII mammary adenocarcinoma model. Rat MDSCs in blood, spleen, bone marrow, and tumor tissue were identified by dual expression of surface markers His48 and CD11b and confirmed to be immunosuppressive upon sorting and interrogation in an in-vitro T cell suppression assay. We find that the percentage of MDSCs (as a proportion of total cells) is reduced in whole spleen isolates (2.55% vs. 19.68%, P≤0.005) and in the circulating white blood cell fraction (1.33% vs. 23.21%, P≤0.05) of exercised versus sedentary animals. In contrast, we find no difference between the proportion of MDSCs as a population of total cells in bone marrow (23.57% vs. 25.52%, P≥0.05) or tumor tissue (11.68% vs. 7.10%, P≥0.05). We conclude that exercise decreases splenic and circulating MDSC populations in tumor bearing animals. Further studies are necessary to establish the molecular mechanisms of this suppression to leverage potential interactions between exercise and MDSC-directed immune therapies.
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Klement, John David, Amy V. Paschall, Natasha M. Savage, Asha Nayak-Kapoor, and Kebin Liu. "5- Fluorouracil regulation of myeloid-derived suppressor cell differentiation in vitro and in vivo." Journal of Immunology 198, no. 1_Supplement (May 1, 2017): 205.5. http://dx.doi.org/10.4049/jimmunol.198.supp.205.5.
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Abstract The chemotherapeutic agent 5-fluorouracil (5-FU) is the standard therapy for patients with advanced colorectal cancer (CRC). 5-FU not only targets tumor cells for apoptosis but also induces apoptosis in myeloid cells, leading to myelosuppression, which has long been thought as a side effect of 5-FU therapy. Myeloid-derived suppressive cells (MDSCs) are a heterogeneous population of immature myeloid cells that exhibit potent suppressive activity to inhibit T and NK cell function. Recent studies have found that 5-FU suppresses MDSCs in mouse models. However, we observed that MDSCs still massively accumulate in human CRC patients after multiple rounds of 5-FU therapy. We hypothesize that a subset of the heterogeneous MDSCs is resistant to 5-FU and that 5-FU therapy selectively eliminates the sensitive MDSCs, enriching the 5-FU-resistant MDSCs. To test this hypothesis, we made use of both in vitro BM-derived MDSC (BM-MDSC) and in vivo mouse tumor models. We observed that 5-FU therapy significantly decreases CD11b+Gr1+ MDSC accumulation in an orthotopic colon cancer mouse model. BM-MDSCs can be induced by cytokines, including GM-CSF, G-CSF, M-CSF and IL-6, either alone or in combination. Cytological analysis indicates that various cytokines induce BM-MDSC to differentially acquire the morphological appearance of myeloid cell subsets, including macrophage- and granulocyte-like cells. Interestingly, all of these BM-derived MDSCs display resistance to 5-FU-induced apoptosis in vitro following exposure to 5-FU at doses as high as 10 μg/mL. Our data indicates that some MDSC subsets display resistance to 5-FU, providing a rationale to explain the enrichment of MDSCs in human CRC patients following successive treatments with 5-FU.
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Bianchi, Anna, Iago De Castro Silva, Nilesh U. Deshpande, Siddharth Mehra, Samara Singh, Austin R. Dosch, Vanessa T. Garrido, et al. "Abstract 2513: MDSC-derived TNF is a novel regulator of T-cell dysfunction in pancreatic cancer." Cancer Research 82, no. 12_Supplement (June 15, 2022): 2513. http://dx.doi.org/10.1158/1538-7445.am2022-2513.
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Abstract Introduction: Abundance of myeloid-derived suppressor cells (MDSC) and a dysfunctional T-cell compartment are defining hallmarks of therapeutic resistance in pancreatic ductal adenocarcinoma (PDAC). Using congenic in vivo murine models to phenocopy extremes of T-cell enrichment or exclusion, we sought to interrogate central MDSC-mediated mechanisms that govern immune tolerance in PDAC. Methods: Orthotopically implanted T-cell-excluded (Tcelllo) vs T-cell-enriched (T-cellhi) congenic KPC tumors, and intratumoral Ly6G+F4/80- MDSCs from both clones, were subjected to RNA sequencing. Ex vivo co-cultures evaluated the effects of intratumoral MDSC on splenic T-cells. Orthotopically injected KPC-T-celllo mice were treated with etanercept vs. vehicle, and immunophenotyping via flow cytometry was performed. Results: RNA-seq of KPC T-celllo vs. T-cellhi tumors revealed enrichment of myeloid immunoregulatory pathways, and downregulation of leukocyte activation/cytotoxicity pathways. Flow cytometry revealed a dramatic increase in MDSCs infiltrating KPC-Tcelllo tumors (P<0.001). To decipher MDSC-intrinsic mechanisms associated with T-cell exclusion, RNA-seq of MDSCs infiltrating T-cellhi clones revealed relative downregulation of MAPK signaling, and cytokine profiling of MDSCs conditioned with MAPK inhibitor trametinib revealed marked reduction in TNF secretion. Confocal microscopy confirmed striking decrease in TNF in MDSCs isolated from KPC- T-cellhi vs. Tcelllo tumors. Ex vivo MDSC-T-cell co-cultures significantly attenuated T-cell proliferation and activation (via IFN-γ release) while favoring T-cell apoptosis, which could be rescued by pre-conditioning MDSCs with either etanercept (TNFR2 decoy receptor) or MAPK pathway inhibitors. Orthotopically injected KPC-T-celllo tumor-bearing mice treated with etanercept demonstrated a remodeled TME vs. vehicle-treated mice, with attenuation in MDSC trafficking, enrichment in CD4+/CD8+ T-cell infiltration, and reduction in T-cell exhaustion. Conclusion: MDSC-derived TNF regulates T-cell dysfunction in PDAC via a MAPK-dependent mechanism. Compartment-specific inhibition of TNF may be a provocative strategy to overcome immune tolerance in PDAC. Citation Format: Anna Bianchi, Iago De Castro Silva, Nilesh U. Deshpande, Siddharth Mehra, Samara Singh, Austin R. Dosch, Vanessa T. Garrido, Christine I. Rafie, Nagaraj Nagathihalli, Nipun Merchant, Jashodeep Datta. MDSC-derived TNF is a novel regulator of T-cell dysfunction in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2513.
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Umemura, Naoki, Masahiro Sugimoto, Yusuke Kitoh, Masanao Saio, and Hiroshi Sakagami. "Metabolomic profiling of tumor-infiltrating macrophages during tumor growth." Cancer Immunology, Immunotherapy 69, no. 11 (June 9, 2020): 2357–69. http://dx.doi.org/10.1007/s00262-020-02622-8.
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Abstract Myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) are both key immunosuppressive cells that contribute to tumor growth. Metabolism and immunity of tumors depend on the tumor microenvironment (TME). However, the intracellular metabolism of MDSCs and TAMs during tumor growth remains unclear. Here, we characterized CD11b+ cells isolated from a tumor-bearing mouse model to compare intratumoral TAMs and intrasplenic MDSCs. Intratumoral CD11b+ cells and intrasplenic CD11b+ cells were isolated from tumor-bearing mice at early and late stages (14 and 28 days post-cell transplantation, respectively). The cell number of intrasplenic CD11b+ significantly increased with tumor growth. These cells included neutrophils holding segmented leukocytes or monocytes with an oval nucleus and Gr-1hi IL-4Rαhi cells without immunosuppressive function against CD8 T cells. Thus, these cells were classified as MDSC-like cells (MDSC-LCs). Intratumoral CD11b+ cells included macrophages with a round nucleus and were F4/80hi Gr-1lo IL-4Rαhi cells. Early stage intratumoral CD11b+ cells inhibited CD8 T cells via TNFα. Thus, this cell population was classified as TAMs. Metabolomic analyses of intratumoral TAMs and MDSC-LCs during tumor growth were conducted. Metabolic profiles of intratumoral TAMs showed larger changes in various metabolic pathways, e.g., glycolysis, TCA cycle, and glutamic acid pathways, during tumor growth compared with MDSL-LCs. Our findings demonstrated that intratumoral TAMs showed an immunosuppressive capacity from the early tumor stage and underwent intracellular metabolism changes during tumor growth. These results clarify the intracellular metabolism of TAMs during tumor growth and contribute to our understanding of tumor immunity.
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Pegues, Melissa A., Ian L. McWilliams, and Alexander J. Szalai. "C-reactive protein exacerbates renal ischemia-reperfusion injury: are myeloid-derived suppressor cells to blame?" American Journal of Physiology-Renal Physiology 311, no. 1 (July 1, 2016): F176—F181. http://dx.doi.org/10.1152/ajprenal.00107.2016.
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Myeloid-derived suppressor cells (MDSCs) are a CD11b+Gr1+ population in mice that can be separated into granulocytic (g-MDSC) and monocytic (m-MDSC) subtypes based on their expression of Ly6G and Ly6C. Both MDSC subtypes are potent suppressors of T cell immunity, and their contribution has been investigated in a plethora of diseases including renal cancer, renal transplant, and chronic kidney disease. Whether MDSCs contribute to the pathogenesis of acute kidney injury (AKI) remains unknown. Herein, using human C-reactive protein (CRP) transgenic (CRPtg) and CRP-deficient mice (CRP−/−) subjected to bilateral renal ischemia-reperfusion injury (IRI), we confirm our earlier finding that CRP exacerbates renal IRI and show for the first time that this effect is accompanied in CRPtg mice by a shift in the balance of kidney-infiltrating MDSCs toward a suppressive Ly6G+Ly6Clow g-MDSC subtype. In CRPtg mice, direct depletion of g-MDSCs (using an anti-Gr1 monoclonal antibody) reduced the albuminuria caused by renal IRI, confirming they play a deleterious role. Remarkably, treatment of CRPtg mice with an antisense oligonucleotide that specifically blocks the human CRP acute-phase response also led to a reduction in renal g-MDSC numbers and improved albuminuria after renal IRI. Our study in CRPtg mice provides new evidence that MDSCs participate in the pathogenesis of renal IRI and shows that their pharmacological depletion is beneficial. If ongoing investigations confirm that CRP is an endogenous regulator of MDSCs in CRPtg mice, and if this action is recapitulated in humans, then targeting CRP or/and MDSCs might offer a new approach for the treatment of AKI.