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Chen, Li, Li Xiong, Shubing Hong, Jin Li, Zijun Huo, Yudong Li, Shuwei Chen, et al. "Circulating Myeloid-derived Suppressor Cells Facilitate Invasion of Thyroid Cancer Cells by Repressing miR-486-3p." Journal of Clinical Endocrinology & Metabolism 105, no. 8 (June 3, 2020): 2704–18. http://dx.doi.org/10.1210/clinem/dgaa344.
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Abstract Background Myeloid-derived suppressor cells (MDSCs) have become increasingly recognized as facilitators of tumor development. However, the role of MDSCs in papillary thyroid carcinoma (PTC) progression has not been clearly explored. Objective We aimed to evaluate the levels and function of circulating MDSCs in PTC. Methods The proportion of circulating polymorphonuclear (PMN)-MDSCs and mononuclear-MDSCs from patients with PTC or benign thyroid nodules and healthy controls was measured using flow cytometry. For immunosuppressive activity analysis, sorted circulating MDSCs were cocultured with CD3/CD28-costimulated T lymphocytes and the proliferation of T cells was determined. PTC cell lines (TPC-1 and BC-PAP) were cocultured with PMN-MDSCs, and the effects on cell migration, invasion, proliferation, and apoptosis were evaluated. The differential expressed microribonucleic acids (RNAs) and messenger RNAs and their function were also explored in TPC-1 cells cocultured with or without PMN-MDSCs. Results PMN-MDSCs were increased in peripheral blood mononuclear cells of patients with PTC. Circulating PMN-MDSCs displayed strong T cell suppressive activity. PTC cells demonstrated enhanced invasive capabilities in vitro and in vivo when cocultured with sorted PMN-MDSCs. PMN-MDSCs decreased expression of miR-486-3p and activated nuclear factor kappa B2 (NF-κB2), a direct target of miR-486-3p. Rescue of miR-486-3p diminished the cell migration and invasion induced by PMN-MDSCs. Conclusion Collectively, our work indicates that circulating PMN-MDSCs promote PTC progression. By suppressing miR-486-3p, PMN-MDSCs promote the activity of the NF-κB2 signaling pathway, resulting in accelerated invasion of PTC cells, which may provide new therapeutic strategies for treatment of thyroid 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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Tian, Xinyu, and Shengjun Wang. "LncRNA AK036396 inhibits maturation and accelerates immunosuppression of polymorphonuclear myeloid-derived suppressor cells by enhancing the stability of ficolin B." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 89.4. http://dx.doi.org/10.4049/jimmunol.204.supp.89.4.
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Abstract Long non-coding RNAs (lncRNAs) are emerging as crucial regulators of cell biology. However, the role of lncRNAs in the development and function of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) remains unclear. Here, we identified that the lncRNA AK036396 was highly expressed in PMN-MDSCs, and lncRNA AK036396 knockdown promoted the maturation and decreased the suppressive function of PMN-MDSCs. Ficolin B (Fcnb), whose expression could be used to reflect PMN-MDSC development, was the predicted target gene of lncRNA AK036396 based on microarray results. LncRNA AK036396 knockdown attenuated Fcnb protein stability in a manner dependent on the ubiquitin-proteasome system. Moreover, Fcnb inhibition downregulated the suppressive function of PMN-MDSCs. In addition, the expression of human M-ficolin, which is an orthologue of mouse Fcnb, was increased and positively correlated with arginase1 (Arg1) level in lung cancer patients. Based on these findings, lncRNA AK036396 can inhibit maturation and accelerate immunosuppression of PMN-MDSCs by enhancing Fcnb protein stability.
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Wang, Shengjun, Xinyu Tian, Tingting Wang, Kai Yin, Dongwei Zhu, Jie Ma, and Huaxi Xu. "LncRNA AK036396/FcnB regulating polymorphonuclear myeloid-derived suppressor cells in tumor bearing mice." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 164.7. http://dx.doi.org/10.4049/jimmunol.204.supp.164.7.
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Abstract Myeloid-derived suppressor cells (MDSCs), which are constituted of immature myeloid cells, represent a population of heterogeneous cells derived from bone marrow. Activated and expanded MDSCs suppress the antitumor immune response by directly inhibiting T cell by high levels of Arg1, reactive oxygen species, and inducible nitric oxide synthase. Long non-coding RNAs (lncRNAs) are transcripts with lengths >200 nts and without the capacity to encode proteins. With the development of RNA sequencing, lncRNAs that were previously considered “transcriptional noise” have been confirmed to be involved in regulating cellular biology. However, the role of lncRNAs in the development and function of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) remains unclear. Here, we identified that the lncRNA AK036396 was highly expressed in PMN-MDSCs, and lncRNA AK036396 knockdown promoted the maturation and decreased the suppressive function of PMN-MDSCs. Ficolin B (Fcnb), whose expression could be used to reflect PMN-MDSC development, was the predicted target gene of lncRNA AK036396 based on microarray results. LncRNA AK036396 knockdown attenuated Fcnb protein stability in a manner dependent on the ubiquitin-proteasome system. Moreover, Fcnb inhibition downregulated the suppressive function of PMN-MDSCs. In addition, the expression of human M-ficolin, which is an orthologue of mouse Fcnb, was increased and positively correlated with arginase1 (Arg1) level in lung cancer patients. Based on these findings, lncRNA AK036396 can inhibit maturation and accelerate immunosuppression of PMN-MDSCs by enhancing Fcnb protein stability, which will be helpful for developing antitumor therapies targeting PMN-MDSCs.
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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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Chen, Huanhuan, Keqing Yang, Lingxiao Pang, Jing Fei, Yongliang Zhu, and Jianwei Zhou. "ANKRD22 is a potential novel target for reversing the immunosuppressive effects of PMN-MDSCs in ovarian cancer." Journal for ImmunoTherapy of Cancer 11, no. 2 (February 2023): e005527. http://dx.doi.org/10.1136/jitc-2022-005527.
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BackgroundOvarian cancer is the deadliest type of malignant gynecological tumor. Polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) are involved ovarian cancer and are closely related to adverse outcomes. However, the immunosuppressive mechanism of PMN-MDSCs remains elusive.MethodsThe types and numbers of ANKRD22-expressing cells were investigated by bioinformatics analysis and immunohistochemical staining.Ankrd22-/-C57BL/6 mice were constructed with CRISPR-Cas9 technology. Mouse PMN-MDSCs were obtained from bone marrow (BM)-derived CD11b+Ly6G+Ly6Clowcells sorted by fluorescence-activated cell sorting with treatment of GM-CSF and IL-6, and the immunosuppressive activity of PMN-MDSCs was evaluated by flow cytometry (FCM) and ELISA. The expression level of CCR2 and the exogenous glucose uptake capacity were determined by FCM. RT-qPCR was used to detectANKRD22expression in CD11b+HLA-DR-CD14-CD15+cells from human ovarian cancer tissues, and the correlations ofANKRD22expression with the clinical characteristics and prognosis of patients were evaluated by the χ2test.ResultsWe identified a novel protein involved in regulating the immunosuppressive ability of PMN-MDSCs, ANKRD22.Ankrd22expression was high in mouse CD11b+Ly6G+Ly6Clowcells and could be significantly downregulated after exposure to a simulated microenvironmental stimulus. Knockout ofAnkrd22increased the expression level of CCR2 of CD11b+Ly6G+Ly6Clowcells and the immunosuppressive activity of PMN-MDSCs. BM-derived CD11b+Ly6G+Ly6Clowcells ofAnkrd22-/-mice significantly promoted the proliferation of ovarian cancer cells in tumor xenograft mouse models. Mechanistically, RNA sequencing showed thatWdfy1expression was obviously increased inAnkrd22-knockout BM-derived CD11b+Ly6G+Ly6Clowcells and that ectopic expression ofWdfy1increased the levels ofArg1,Inos,IdoandPdl1inAnkrd22+/+PMN-MDSCs derived from BM-derived CD11b+Ly6G+Ly6Clowcells. Surprisingly, an ANKRD22-activating candidate small-molecule compound attenuated the immunosuppressive activity ofAnkrd22+/+PMN-MDSCs. Finally, we found that lowANKRD22levels in CD11b+HLA-DR-CD14-CD15+cells derived from primary ovarian tissues were associated with a more advanced International Federation of Gynecology and Obstetrics stage, a higher recurrence rate, and a higher neutrophil-to-lymphocyte ratio.ConclusionsThese results suggest that ANKRD22 is a potential novel target for reversing the immunosuppressive effects of PMN-MDSCs.
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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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Liu, Wangkai, Sitao Li, Yushan Li, Wei Shen, Haitian Chen, Xiaoyu Li, Linnuan Cai, et al. "Decreased Polymorphonuclear Myeloid-Derived Suppressor Cells and ROS Production Correlated Closely with Bronchopulmonary Dysplasia in Preterm Infants." Oxidative Medicine and Cellular Longevity 2022 (September 20, 2022): 1–8. http://dx.doi.org/10.1155/2022/9010354.
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Background. Bronchopulmonary dysplasia (BPD) is one of the most serious complications in premature infants. Myeloid-derived suppressor cells (MDSCs) have been indicated to promote immune tolerance and induce anti-inflammatory responses during the neonatal stage. However, the role of MDSCs in BPD has not been completely expounded. Methods. 130 cases of newborns were collected from six tertiary hospitals in Guangzhou from August 2019 to June 2022. They were divided into BPD group, non-BPD preterm infants group, and term infants group according to gestational age and presence of BPD. The peripheral blood was collected and used to analyze the proportion, phenotypic, and function of MDSCs at 3 to 7 days and 8 to 14 days after birth, respectively. Results. We indicated that the number of both MDSCs in premature infants is reduced, and the number of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) in peripheral blood of BPD infants was significantly lower than that of non-BPD infants under 34 weeks of gestational age ( P < 0.05 ). Furthermore, PMN-MDSCs from peripheral blood of patients presented inhibitory effect on proliferation of CD4+T and CD8+T cells in each group. However, PMN-MDSCs from BPD group had obviously weaker inhibitory effect on proliferation of CD4+T and CD8+T cells than that from non-BPD preterm infants group. In addition, we demonstrated that the expression of NADPH oxidase (Nox2) and reactive oxygen species (ROS) in PMN-MDSCs of BPD children was significantly lower than that in non-BPD preterm infants, suggesting that ROS pathway was affected in BPD in premature infants. Conclusion. This study preliminarily revealed the role of PMN-MDSCs in the pathogenesis of BPD in premature infants. The specific immune regulation mechanism of PMN-MDSCs in BPD will provide new ideas and strategies for clinical prevention and treatment of BPD in premature infants.
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Cheng, Xiang, Hongji Zhang, Allan Tsung, and Hai Huang. "Abstract 2544: Preoperative exercise inhibits hepatic metastasis by suppressing PMN-MDSC formation of NETs." Cancer Research 82, no. 12_Supplement (June 15, 2022): 2544. http://dx.doi.org/10.1158/1538-7445.am2022-2544.
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Abstract Introduction: Under surgical trauma, the pathological amplification and activation of neutrophils with potent immunosuppressive functions, also known as polymorphonuclear myeloid-derived suppressive cells (PMN-MDSCs), can promote metastasis by forming neutrophil extracellular traps (NETs) that are web-like structures consisting of nuclear DNA, histones, and granule proteins. Preoperative exercise (PEx) reduces postoperative complications with improved clinical outcomes in cancer patients undergoing surgeries. are. Our preliminary data show that PEx suppresses liver ischemia/reperfusion (I/R)-induced colorectal cancer (CRC) liver metastasis. Our recent studies have shown I/R-induced NETs promote liver CRC metastasis by capturing tumor cells and preventing infiltration and cytotoxicity of CD8+ T cells in tumor microenvironment (TME). We hypothesize that PEx remodels the TME by suppressing PMN-MDSCs formation of NETs. Methods: Male mice were subjected to exercise for 4 weeks, before MC38 colorectal cancer cells were injected through portal vein, and then subjected to 70% partial liver warm I/R as surgical stress. The single-cell RNA sequencing (scRNA-seq) was performed on CD45+leukocytes from TME 3 weeks after surgery. Immunofluorescence staining and Western Blot were used to determine NETs formation in the TME. Flow cytometry was used to determine the infiltration of PMN-MDSCs and CD8+ T lymphocytes in the tumors. Results: Our scRNA-seq data reveal that PEx leads to a remarkable transcriptomic shift in most immune cells types, such as PMN-MDSCs, M-MDSCs, T cells, Kupffer cells, B cells, NK and NKT cells, in the TME. PEx decreases the percentages of PMN-MDSCs in the TME and inhibits theNETs formation by PMN-MDSCs. scRNA-seq shows a significant increase of the chemokines CXCL10 in PEx-trained PMN-MDSCs obtained 3 weeks after I/R-induced hepatic metastasis, compared with sedentary controls. In addition, PEx increases the number of CD8+ T lymphocytes infiltrating the TME. Summary: Our study shows that PEx downregulates NETs formation and increases the CXCL10 expression in PMN-MDSCs, thus promoting the recruitment more cytotoxic CD8 T lymphocytes to suppress tumor metastasis. Citation Format: Xiang Cheng, Hongji Zhang, Allan Tsung, Hai Huang. Preoperative exercise inhibits hepatic metastasis by suppressing PMN-MDSC formation of NETs [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 2544.
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Bizymi, Nikoleta, Athina Damianaki, Maria Velegraki, Konstantina Zavitsanou, Anastasios Karasachinidis, Anthie Georgopoulou, Irene Mavroudi, et al. "Frequency and Functional Analysis of Myeloid-Derived Suppressor Cells (MDSCs) in the Peripheral Blood and Bone Marrow of Patients with Chronic Idiopathic Neutropenia (CIN)." Blood 136, Supplement 1 (November 5, 2020): 26–27. http://dx.doi.org/10.1182/blood-2020-136500.
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Myeloid-derived suppressor cells (MDSCs) are myeloid cells with immunoregulatory properties characterized mainly by suppression of T-cell responses (Bizymi et al, HemaSphere 2019). They are divided in HLA-DRlow/-/CD11b+/CD33+/CD15+ polymorphonuclear (PMN-MDSCs) and HLA-DRlow/-/CD11b+/CD33+/CD14+ monocytic (M-MDSCs) subsets and they are implicated in inflammatory and malignant diseases. Chronic idiopathic neutropenia (CIN), is a (usually benign) neutrophil disorder characterized by persistent and unexplained neutropenia following a detailed clinical/laboratory investigation including anti-neutrophil antibody testing, bone marrow (BM) biopsy and karyotype (Dale & Bolyard, Curr Opin Hematol 2017). Previous studies have shown that neutropenia in CIN is associated with increased apoptosis of BM granulocytic progenitor cells due to an inflammatory BM microenvironment consisting of oligoclonal T-lymphocytes, proinflammatory monocytes and proapoptotic cytokines. The aim of the present study is to explore the possible involvement of the MDSCs in the pathophysiology of CIN by investigating their number in peripheral blood (PB) and BM in association with their functional characteristics. We have studied 100 CIN patients and 49 age- and sex-matched healthy controls. The patients fulfilled the previously described diagnostic criteria for CIN (Papadaki et al, Blood 2003) and had mean neutrophil counts 1095.67 ± 479.52 (median 1215, range 100-1700). MDSC subsets were quantitated by flow cytometry in the PB mononuclear cell (PBMC) fraction using the combination of CD33PC7/CD15PC5/HLA-DRECD/CD14PE/CD11bFITC monoclonal antibodies and the Kaluza analysis software. MDSC subsets were also studied in the BMMC fraction of 24 CIN patients and 8 healthy controls from the study population. The T-cell suppression function of patient MDSCs was evaluated in coculture experiments of immunomagnetically sorted, CFSE stained, normal CD3+ cells with immunomagnetically sorted M-MDSCs and PMN-MDSCs from 4 patients and 4 healthy donors using recombinant human IL-2 as activating factor. CFSE staining was detected in the CD3+ cells on day 0 and day 3 of coculture and analysis was performed with the Fcs Express 7 software. Statistical analysis was performed with the Statistica software. We found that the proportion of PB M-MDSCs was statistically significant lower in CIN patients (1.45% ± 1.82%) compared to controls (3.68% ± 3.12%, Mann-Whitney test, p < 0.0001) (Figure a) whereas the proportion of PB PMN-MDSCs, although lower in patients, did not differ significantly from the controls. The proportion of BM M-MDSCs did not differ significantly between CIN patients and controls whereas the proportion of BM PMN-MDSCs was statistically significant lower in patients (13.27% ± 11.27%) compared to controls (19.49% ± 4.46%; Mann-Whitney test, p = 0.0291) (Figure b). Paired analysis showed that the proportion of PMN-MDSCs were higher in the BMMC compared to PBMC fraction in both CIN patients (13.27% ± 11.27% vs 1.14% ± 1.64%, respectively; Wilcoxon test, p = 0.005) (Figure c) and healthy controls (19.49% ± 4.46% vs 9.92% ± 9.08%, respectively; Wilcoxon test, p = 0.0118). Interestingly, the proportion of increase of PMN-MDSCs (in BMMC vs PBMC fraction) was significantly higher in patients (86.71% ± 21.26%) compared to controls (55.95% ± 38.59%; Mann-Whitney test, p = 0.0357) (Figure d). The above data indicate low production of PMN-MDSCs in CIN patients compared to controls but a trend for accumulation of these cells in patients' BM. No statistically significant difference was documented in paired analysis of M-MDSCs between BMMC and PBMC fractions in either CIN patients or healthy controls. Patient PMN-MDSCs and M-MDSCs displayed normal capacity to suppress T-cell proliferation as was indicated by the T-cell generations in coculture experiments of normal CD3+ cells in the presence or absence of patient MDSCs (Figure e). In conclusion, CIN patients display low proportion of MDSCs in the PB and lower proportion of PMN-MDSC in the BM compared to normal individuals. Patient MDSCs display normal capacity to suppress T-cell activation. The low proportions of MDSCs may sustain the inflammatory process associated with CIN whereas the accumulation of PMN-MDSCs in the BM represents probably a compensatory mechanism to suppress the inflammatory processes within patients' BM microenvironment. Figure Disclosures Papadaki: Genesis pharma SA: Membership on an entity's Board of Directors or advisory committees, Research Funding.
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Li, Congcong, Chao Chen, Xiaomin Kang, Xiaoxin Zhang, Si Sun, Feng Guo, Qiaohong Wang, Xi Kou, Wenxin Bai, and Aimin Zhao. "Decidua-derived granulocyte macrophage colony-stimulating factor induces polymorphonuclear myeloid-derived suppressor cells from circulating CD15+ neutrophils." Human Reproduction 35, no. 12 (October 15, 2020): 2677–91. http://dx.doi.org/10.1093/humrep/deaa217.
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Abstract STUDY QUESTION Do decidua-derived factors stimulate the conversion of circulating neutrophils to polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) in early human pregnancy? SUMMARY ANSWER Circulating neutrophils can acquire PMN-MDSC-like phenotypes and function via phosphorylated signal transducer and activator of transcription 5/programmed death ligand 2 (pSTAT5/PD-L2) signalling after stimulation with decidua-derived granulocyte macrophage colony-stimulating factor (GM-CSF). WHAT IS KNOWN ALREADY PMN-MDSCs are an important immunoregulatory cell type in early pregnancy. Neutrophils are of high heterogeneity and plasticity and can polarize to immunosuppressive PMN-MDSCs upon stimulation. STUDY DESIGN, SIZE, DURATION For analysis of myeloid-derived suppressor cell (MDSC) subset proportions, 12 endometrium tissues and 12 peripheral blood samples were collected from non-pregnant women, and 40 decidua tissues and 16 peripheral blood samples were obtained from women with normal early pregnancy undergoing elective surgical pregnancy termination for nonmedical reasons with gestation age of 6–10 weeks. Twenty-nine decidua tissues were collected for isolation of CD15+ PMN-MDSCs. Twenty endometrium tissues and 30 decidua tissues were collected for cytokine analysis, immunohistochemistry or neutrophil stimulation. Peripheral blood samples were obtained from 36 healthy donors for isolation of CD3+ T cells and CD15+ neutrophils. PARTICIPANTS/MATERIALS, SETTING, METHODS The proportion of MDSC subsets in the decidua and peripheral blood of normal early pregnancy, endometrium and peripheral blood of non-pregnant women was analysed by flow cytometry. The phenotypes and function of decidual PMN-MDSCs and circulating neutrophils were compared by flow cytometry. Circulating neutrophils were stimulated with decidual explant supernatant (DES) and the phenotypes were measured by flow cytometry and immunofluorescence. The suppressive capacity of decidual PMN-MDSCs and DES-conditioned neutrophils was analysed by flow cytometry with or without anti-programmed cell death-1 (PD-1) antibody. Cytokines from DES and endometrial explant supernatant (EES) were detected by a Luminex assay. GM-CSF expression was determined by ELISA and immunohistochemistry. Neutrophils were stimulated with DES, EES, DES with anti-GM-CSF antibody or EES with GM-CSF. CD11b, lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), PD-L2 and pSTAT5 expression were measured by flow cytometry. MAIN RESULTS AND THE ROLE OF CHANCE The frequency of PMN-MDSCs was significantly increased in the decidua of early pregnancy compared with peripheral blood of non-pregnant women, the endometrium of non-pregnant women or peripheral blood during early pregnancy. Decidual PMN-MDSCs suppressed T-cell proliferation and cytokine production. Phenotypes of decidual PMN-MDSCs were similar to mature activated neutrophils. DES-induced CD11b, LOX-1, PD-L2 expression and STAT5 phosphorylation in neutrophils. The PD-L2 expression in neutrophils was dependent on STAT5 phosphorylation. Both decidual PMN-MDSCs and DES-conditioned neutrophils suppressed T-cell proliferation via PD-1 signalling. GM-CSF was up-regulated in the decidua and induced CD11b, LOX-1 and PD-L2 expression on neutrophils. DES significantly induced CD11b, LOX-1, PD-L2 expression and STAT5 phosphorylation. Anti-GM-CSF antibody remarkably blocked such stimulation in neutrophils. EES did not induce CD11b, LOX-1, PD-L2 expression or STAT5 phosphorylation, while GM-CSF treatment sufficiently stimulated CD11b, LOX-1, PD-L2 expression and STAT5 phosphorylation in neutrophils. LARGE SCALE DATA N/A LIMITATIONS, REASONS FOR CAUTION The study was based on in vitro experiments and we were not able to evaluate neutrophils differentiation to PMN-MDSCs in other sites before entering the maternal–foetal interface due to the limited availability of human samples. This needs to be explored using murine models. WIDER IMPLICATIONS OF THE FINDINGS This is the first study demonstrating that decidual PMN-MDSCs are a group of immunoregulatory cells with mature status, and that neutrophils can be induced to a PMN-MDSC-like phenotype with decidua-derived GM-CSF via pSTAT5/PD-L2 signalling. This study indicates that GM-CSF can facilitate immune tolerance of early pregnancy through regulating PMN-MDSCs and further provides a potential role of GM-CSF in prevention and treatment for pregnancy complications. STUDY FUNDING/COMPETING INTEREST(S) This work was supported by the National Natural Science Foundation of China (81671481) and National Natural Science Foundation of China (81871179). All authors have no competing interests to declare.
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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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Yao, G., S. Wang, and L. Sun. "THU0226 MESENCHYMAL STEM CELL TRANSPLANTATION AMELIORATES EXPERIMENTAL SJÖGREN’S SYNDROME BY DOWNREGUALTING MDSCS VIA COX2/PGE2 PATHWAY." Annals of the Rheumatic Diseases 79, Suppl 1 (June 2020): 340.1–340. http://dx.doi.org/10.1136/annrheumdis-2020-eular.1391.
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Background:Although mesenchymal stem cells (MSCs) transplantation have been demonstrated to be an effective therapeutic approach to treat experimental Sjögren’s syndrome (ESS)1, the specific underlying mechanisms remain to be elucidated. Myeloid-derived suppressor cells (MDSCs) were significantly increased with decreased suppressive capacity during disease development in ESS2-3. However, the therapeutic effects and mechanisms by which MSCs regulating MDSCs in SS still remain unknown.Objectives:Here we aim to explore whether regulation of MDSCs was responsible for the beneficial effects of MSC transplantation on SS.Methods:The MSCs were infused intonon-obese diabetic (NOD) mice via the tail vein. The histological features of submandibular glands, lung, saliva flow rate were evaluated. The number and immune-suppressive activity of MDSCs, the subsets of MDSCs, polymorphonuclear MDSCs (PMN-MDSCs) and monocytic-MDSCs (M-MDSCs) in NOD mice were determined. The bone marrow cells under MDSCs differentiation conditions were co-cultured with or without MSCs. The COX2 inhibitor NS-398, anti-TGF-β1, or anti-IFN-β antibodies were added to coculture medium of MSCs and MDSCs induced from bone marrow cells respectively.Results:We found that MDSCs in bone marrow and peripheral blood increased in ESS mice. MSC transplantation ameliorated SS-like syndrome and down-regulated the percentages of MDSCs, PMN-MDSCs and M-MDSCs and promoted their suppressive ability in ESS mice significantly (Figure 1). In vitro, MSCs could down-regulate the differentiation and up-regulate the suppressive ability of MDSCs. Mechanistically, MSCs inhibited the differentiation of MDSCs and PMN-MDSCs via secreting prostaglandin E2, and inhibited the differentiation of M-MDSCs by secreting interferon-β (Figure 2).Figure 1.MSCs ameliorated SS symptoms and decreased MDSCs in NOD mice.Figure 2.MSCs inhibited the differentiation of PMN-MDSCs and M-MDSCs by COX2/PGE2 and IFN-β respectively.Conclusion:Our findings suggested that MSCs alleviated SS-like symptoms by suppressing the aberrant accumulation and improving the suppressive function of MDSCs in ESS mice via COX2/PGE2 pathway.References:[1]Shi B, Qi J, Yao G, et al. Mesenchymal stem cell transplantation ameliorates Sjögren’s syndrome via suppressing IL-12 production by dendritic cells. Stem Cell Res Ther, 2018; 9(1):308.[2]Qi J, Li D, Shi G, et al. Myeloid-derived suppressor cells exacerbates Sjögren’s syndrome by inhibiting Th2 immune responses. Mol Immunol, 2018; 101:251-258.[3]Tian J, Rui K, Hong Y, et al. Increased GITRL impairs the function of myeloid-derived suppressor cells and exacerbates primary Sjögren’s syndrome. J Immunol, 2019; 202(6):1693-1703.Disclosure of Interests:None declared
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Kim, Rina, Ayumi Hashimoto, Nune Markosyan, Vladimir A. Tyurin, Yulia Y. Tyurina, Shuyu Fu, Mohit Sehgal, et al. "Abstract C046: Polymorphonuclear myeloid derived suppressor cells die by ferroptosis in the tumor microenvironment." Cancer Research 82, no. 22_Supplement (November 15, 2022): C046. http://dx.doi.org/10.1158/1538-7445.panca22-c046.
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Abstract Myeloid-derived suppressor cells (MDSC) in the tumor microenvironment (TME) function as an immunosuppressive shield that protects the tumor from the host’s immune system and considered a barrier to effective immunotherapy. Here, we focused on polymorphonuclear (PMN)-MDSCs, the most prevalent MDSCs in the TME, to identify mechanisms regulating their maintenance, turnover, and accumulation. Using four mouse models of cancer including autochthonous pancreatic adenocarcinoma from KPC genetically engineered mice (KrasG12D/p53R172H, PdxCre), we found that PMN-MDSCs spontaneously die by ferroptosis, a non-apoptotic form of regulated cell death triggered by the discoordination of regulatory redox mechanisms culminating in massive peroxidation of polyunsaturated phospholipids. Only PMN-MDSCs within the TME were observed to spontaneously undergo ferroptosis. In mice, ferroptosis-related gene expression in CD11b+L6ClowLy6G+ PMN-MDSC isolated from bone marrow, spleen, and tumor demonstrated tumor-specific ferroptosis across tumor models. In humans, whole transcriptomic analysis of PMN-MDSC sorted from tumors and matched blood of lung cancer patients vs blood of healthy donors revealed up-regulation of genes involved in the regulation of ferroptosis in tumor PMN-MDSC. Ferroptosis gene signatures correlated with the PMN-MDSC signatures in pancreatic cancer patients and was associated with worse overall survival. Thus, ferroptosis is an unappreciated, prominent pathway of cell death of PMN-MDSCs in cancer linked to clinical outcome in patients with pancreatic cancer. Citation Format: Rina Kim, Ayumi Hashimoto, Nune Markosyan, Vladimir A. Tyurin, Yulia Y. Tyurina, Shuyu Fu, Mohit Sehgal, Laura Garcia-Gerique, Gozde Kar, Andrew Kossenkov, Bereket A. Gebregziabher, John W. Tobias, Kristin Hicks, Hui Deng, Laxminarasimha Donthireddy, Andrew Greenberg, Brian Nam, Yulia Nefedova, Valerian E. Kagan, Robert H. Vonderheide, Dmitry Gabrilovich. Polymorphonuclear myeloid derived suppressor cells die by ferroptosis in the tumor microenvironment [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr C046.
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Jensen, Kent P., David A. Hongo, XuHuai Ji, PingPing Zheng, Rahul D. Pawar, Thomas Hsin-Hsu Wu, Stephan Busque, et al. "Development of immunosuppressive myeloid cells to induce tolerance in solid organ and hematopoietic cell transplant recipients." Blood Advances 5, no. 17 (August 25, 2021): 3290–302. http://dx.doi.org/10.1182/bloodadvances.2020003669.
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Abstract Replacement of failed organs followed by safe withdrawal of immunosuppressive drugs has long been the goal of organ transplantation. We studied changes in the balance of T cells and myeloid cells in the blood of HLA-matched and -mismatched patients given living donor kidney transplants followed by total lymphoid irradiation, anti-thymocyte globulin conditioning, and donor hematopoietic cell transplant to induce mixed chimerism and immune tolerance. The clinical trials were based on a conditioning regimen used to establish mixed chimerism and tolerance in mice. In preclinical murine studies, there was a profound depletion of T cells and an increase in immunosuppressive polymorphonuclear (pmn) myeloid-derived suppressor cells (MDSCs) in the spleen and blood following transplant. Selective depletion of pmn MDSCs in mice abrogated mixed chimerism and tolerance. In our clinical trials, patients given an analogous tolerance conditioning regimen developed similar changes, including profound depletion of T cells and a marked increase in MDSCs in blood posttransplant. Posttransplant pmn MDSCs transiently increased expression of lectin-type oxidized LDL receptor-1, a marker of immunosuppression, and production of the T-cell inhibitor arginase-1. These posttransplant pmn MDSCs suppressed the activation, proliferation, and inflammatory cytokine secretion of autologous T-cell receptor microbead-stimulated pretransplant T cells when cocultured in vitro. In conclusion, we elucidated changes in receptors and function of immunosuppressive myeloid cells in patients enrolled in the tolerance protocol that were nearly identical to those of MDSCs required for tolerance in mice. These trials were registered at www.clinicaltrials.gov as #NCT00319657 and #NCT01165762.
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Gondois-Rey, Françoise, Magali Paul, Florence Alcaraz, Sarah Bourass, Jilliana Monnier, Nausicaa Malissen, Jean-Jacques Grob, et al. "Identification of an Immature Subset of PMN-MDSC Correlated to Response to Checkpoint Inhibitor Therapy in Patients with Metastatic Melanoma." Cancers 13, no. 6 (March 17, 2021): 1362. http://dx.doi.org/10.3390/cancers13061362.
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PMN-MDSCs support tumor progression and resistance to ICI therapy through their suppressive functions but their heterogeneity limits their use as biomarkers in cancer. Our aim was to investigate the phenotypic and functional subsets of PMN-MDSCs to identify biomarkers of response to ICI therapy. We isolated low-density CD15+ PMNs from patients with metastatic melanoma and assessed their immune-suppressive capacities. Expression of CD10 and CD16 was used to identify mature and immature subsets and correlate them to inhibition of T cell proliferation or direct cytotoxicity. Frequencies of the PMN-MDSCs subsets were next correlated to the radiological response of 36 patients receiving ICI therapy. Mature activated cells constituted the major population of PMN-MDSCs. They were found in a higher proportion in the pre-treatment blood of patients non responders to ICI. A subset of immature cells characterized by intermediate levels of CD10 and CD16, the absence of expression of SIRPα and a strong direct cytotoxicity to T cells was increased in patients responding to ICI. The paradoxical expansion of such cells during ICI therapy suggests a role of PMNs in the inflammatory events associated to efficient ICI therapy and the usefulness of their monitoring in patients care.
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Mastio, Jérôme, Thomas Condamine, George Dominguez, Andrew V. Kossenkov, Laxminarasimha Donthireddy, Filippo Veglia, Cindy Lin, et al. "Identification of monocyte-like precursors of granulocytes in cancer as a mechanism for accumulation of PMN-MDSCs." Journal of Experimental Medicine 216, no. 9 (June 25, 2019): 2150–69. http://dx.doi.org/10.1084/jem.20181952.
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We have identified a precursor that differentiates into granulocytes in vitro and in vivo yet belongs to the monocytic lineage. We have termed these cells monocyte-like precursors of granulocytes (MLPGs). Under steady state conditions, MLPGs were absent in the spleen and barely detectable in the bone marrow (BM). In contrast, these cells significantly expanded in tumor-bearing mice and differentiated to polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs). Selective depletion of monocytic cells had no effect on the number of granulocytes in naive mice but decreased the population of PMN-MDSCs in tumor-bearing mice by 50%. The expansion of MLPGs was found to be controlled by the down-regulation of Rb1, but not IRF8, which is known to regulate the expansion of PMN-MDSCs from classic granulocyte precursors. In cancer patients, putative MLPGs were found within the population of CXCR1+CD15−CD14+HLA-DR−/lo monocytic cells. These findings describe a mechanism of abnormal myelopoiesis in cancer and suggest potential new approaches for selective targeting of MDSCs.
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Saito, Masafumi, Yutaka Sugita, Kimihiro Yamashita, Mitsugu Fujita, Kota Yamada, Kyosuke Agawa, Akihiro Watanabe, et al. "Abstract 2519: Polymorphonuclear myeloid-derived suppressor cells reflect the status of peritoneal dissemination in colon cancer mouse model." Cancer Research 82, no. 12_Supplement (June 15, 2022): 2519. http://dx.doi.org/10.1158/1538-7445.am2022-2519.
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Abstract Background 8.3% of colorectal cancer (CRC) patients have peritoneal dissemination (PD) and their prognosis is poor. Myeloid-derived suppressor cells, MDSC, are functional myeloid cells with immune suppressive properties. When infiltrated into the tumor, these cells induce dysfunction of cytotoxic T cells via the secretion of immunosuppressive molecules like arginase-1 and promote tumor progression. MDSC is classified into two major subsets in a mouse by their surface antigens: monocytic MDSCs (M-MDSCs; CD11b+Ly6ChighLy6G−) and polymorphonuclear MDSCs (PMN-MDSCs; CD11b+Ly6ClowLy6G+). To date, MDSCs are difficult to identify because they express the same surface markers as neutrophils and monocytes, respectively. CD244, an immunoregulatory transmembrane receptor molecule, has been highlighted as a surface antigen to distinguish PMN-MDSCs from normal neutrophils. However, few studies have demonstrated whether and how MDSCs, especially CD244+ PMN-MDSC, affect the generation and progression of PD. Objective To clarify CD244+ PMN-MDSC affects the progression of PD and CD8+ T cells. Methods Female C57BL6J mice were injected 5.0×105 ~ 2.0×106 cells of MC38 colon cancer intraperitoneally to establish the PD model, and we had conducted the following three experiments: Exp. 1) Investigation of the trend of immune cells including MDSC and CD8+ T cell in the PD nodule, peritoneal cavity, blood, and spleen; Exp. 2) PMN-MDSC depletion test in PD model; and Exp. 3) Investigation of direct influence of CD244+ or CD244- Ly6G+ cells in T cell proliferation in vitro. Results Exp. 1) PD nodules became enlarged and increased over time. All mice had died by day 40 after the cancer was inoculated in the PD model, which was significantly shorter than the MC38-based subcutaneously inoculation model. In the PD model, a significant increase of PMN-MDSCs was observed in the peritoneal cavity, blood, and spleen, and also observed these cells in the PD nodule at day 20. Of note, the CD244+ PMN-MDSC predominantly existed in the population of myeloid cells in the peritoneal cavity. Exp. 2) To deplete the PMN-MDSC, the mice were administered a Ly6G antibody. Although Ly6G treatment could not improve the survival rate of the PD model, the tumor progression was significantly decreased, and the number of both CD4+ T cells and CD8+ T cells was notably increased in the peritoneal cavity at day 19. Exp. 3) Finally, we sorted CD244+/CD244- Ly6G+ cells and co-cultured them with splenocytes. The Ly6G+CD244+ cells significantly inhibited antigen-specific CD8+ T cell proliferation in a dose-dependent manner. T cell suppression mediated by the Ly6G+CD244+ cells was also observed in the numerical evaluation of CD8+ T cells at a high (1:1) ratio. Conclusion The targeted therapy for PMN-MDSCs would provide not only new therapeutic value but also a novel strategy to synergize with T cell-based immunotherapy for CRC-derived PD. Citation Format: Masafumi Saito, Yutaka Sugita, Kimihiro Yamashita, Mitsugu Fujita, Kota Yamada, Kyosuke Agawa, Akihiro Watanabe, Eiji Fukuoka, Shingo Kanaji, Taro Oshikiri, Takeru Matsuda, Yoshihiro Kakeji. Polymorphonuclear myeloid-derived suppressor cells reflect the status of peritoneal dissemination in colon cancer mouse model [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 2519.
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Holokai, Loryn, Jayati Chakrabarti, Joanne Lundy, Daniel Croagh, Pritha Adhikary, Scott S. Richards, Chantal Woodson, et al. "Murine- and Human-Derived Autologous Organoid/Immune Cell Co-Cultures as Pre-Clinical Models of Pancreatic Ductal Adenocarcinoma." Cancers 12, no. 12 (December 17, 2020): 3816. http://dx.doi.org/10.3390/cancers12123816.
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Purpose: Pancreatic ductal adenocarcinoma (PDAC) has the lowest five-year survival rate of all cancers in the United States. Programmed death 1 receptor (PD-1)-programmed death ligand 1 (PD-L1) immune checkpoint inhibition has been unsuccessful in clinical trials. Myeloid-derived suppressor cells (MDSCs) are known to block anti-tumor CD8+ T cell immune responses in various cancers including pancreas. This has led us to our objective that was to develop a clinically relevant in vitro organoid model to specifically target mechanisms that deplete MDSCs as a therapeutic strategy for PDAC. Method: Murine and human pancreatic ductal adenocarcinoma (PDAC) autologous organoid/immune cell co-cultures were used to test whether PDAC can be effectively treated with combinatorial therapy involving PD-1 inhibition and MDSC depletion. Results: Murine in vivo orthotopic and in vitro organoid/immune cell co-culture models demonstrated that polymorphonuclear (PMN)-MDSCs promoted tumor growth and suppressed cytotoxic T lymphocyte (CTL) proliferation, leading to diminished efficacy of checkpoint inhibition. Mouse- and human-derived organoid/immune cell co-cultures revealed that PD-L1-expressing organoids were unresponsive to nivolumab in vitro in the presence of PMN-MDSCs. Depletion of arginase 1-expressing PMN-MDSCs within these co-cultures rendered the organoids susceptible to anti-PD-1/PD-L1-induced cancer cell death. Conclusions: Here we use mouse- and human-derived autologous pancreatic cancer organoid/immune cell co-cultures to demonstrate that elevated infiltration of polymorphonuclear (PMN)-MDSCs within the PDAC tumor microenvironment inhibit T cell effector function, regardless of PD-1/PD-L1 inhibition. We present a pre-clinical model that may predict the efficacy of targeted therapies to improve the outcome of patients with this aggressive and otherwise unpredictable malignancy.
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Oliver, Liliana, Rydell Alvarez, Raquel Diaz, Anet Valdés, Sean H. Colligan, Michael J. Nemeth, Danielle Y. F. Twum, et al. "Mitigating the prevalence and function of myeloid-derived suppressor cells by redirecting myeloid differentiation using a novel immune modulator." Journal for ImmunoTherapy of Cancer 10, no. 9 (September 2022): e004710. http://dx.doi.org/10.1136/jitc-2022-004710.
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BackgroundImmune suppression is common in neoplasia and a major driver is tumor-induced myeloid dysfunction. Yet, overcoming such myeloid cell defects remains an untapped strategy to reverse suppression and improve host defense. Exposure of bone marrow progenitors to heightened levels of myeloid growth factors in cancer or following certain systemic treatments promote abnormal myelopoiesis characterized by the production of myeloid-derived suppressor cells (MDSCs) and a deficiency in antigen-presenting cell function. We previously showed that a novel immune modulator, termed ‘very small size particle’ (VSSP), attenuates MDSC function in tumor-bearing mice, which was accompanied by an increase in dendritic cells (DCs) suggesting that VSSP exhibits myeloid differentiating properties. Therefore, here, we addressed two unresolved aspects of the mechanism of action of this unique immunomodulatory agent: (1) does VSSP alter myelopoiesis in the bone marrow to redirect MDSC differentiation toward a monocyte/macrophage or DC fate? and (2) does VSSP mitigate the frequency and suppressive function of human tumor-induced MDSCs?MethodsTo address the first question, we first used a murine model of granulocyte-colony stimulating factor-driven emergency myelopoiesis following chemotherapy-induced myeloablation, which skews myeloid output toward MDSCs, especially the polymorphonuclear (PMN)-MDSC subset. Following VSSP treatment, progenitors and their myeloid progeny were analyzed by immunophenotyping and MDSC function was evaluated by suppression assays. To strengthen rigor, we validated our findings in tumor-bearing mouse models. To address the second question, we conducted a clinical trial in patients with metastatic renal cell carcinoma, wherein 15 patients were treated with VSSP. Endpoints in this study included safety and impact on PMN-MDSC frequency and function.ResultsWe demonstrated that VSSP diminished PMN-MDSCs by shunting granulocyte-monocyte progenitor differentiation toward monocytes/macrophages and DCs with heightened expression of the myeloid-dependent transcription factors interferon regulatory factor-8 and PU.1. This skewing was at the expense of expansion of granulocytic progenitors and rendered the remaining MDSCs less suppressive. Importantly, these effects were also demonstrated in a clinical setting wherein VSSP monotherapy significantly reduced circulating PMN-MDSCs, and their suppressive function.ConclusionsAltogether, these data revealed VSSP as a novel regulator of myeloid biology that mitigates MDSCs in cancer patients and reinstates a more normal myeloid phenotype that potentially favors immune activation over immune suppression.
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Moorman, Hannah R., Yazmin Reategui, Dakota B. Poschel, and Kebin Liu. "IRF8: Mechanism of Action and Health Implications." Cells 11, no. 17 (August 24, 2022): 2630. http://dx.doi.org/10.3390/cells11172630.
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Interferon regulatory factor 8 (IRF8) is a transcription factor of the IRF protein family. IRF8 was originally identified as an essentialfactor for myeloid cell lineage commitment and differentiation. Deletion of Irf8 leads to massive accumulation of CD11b+Gr1+ immature myeloid cells (IMCs), particularly the CD11b+Ly6Chi/+Ly6G− polymorphonuclear myeloid-derived suppressor cell-like cells (PMN-MDSCs). Under pathological conditions such as cancer, Irf8 is silenced by its promoter DNA hypermethylation, resulting in accumulation of PMN-MDSCs and CD11b+ Ly6G+Ly6Clo monocytic MDSCs (M-MDSCs) in mice. IRF8 is often silenced in MDSCs in human cancer patients. MDSCs are heterogeneous populations of immune suppressive cells that suppress T and NK cell activity to promote tumor immune evasion and produce growth factors to exert direct tumor-promoting activity. Emerging experimental data reveals that IRF8 is also expressed in non-hematopoietic cells. Epithelial cell-expressed IRF8 regulates apoptosis and represses Osteopontin (OPN). Human tumor cells may use the IRF8 promoter DNA methylation as a mechanism to repress IRF8 expression to advance cancer through acquiring apoptosis resistance and OPN up-regulation. Elevated OPN engages CD44 to suppress T cell activation and promote tumor cell stemness to advance cancer. IRF8 thus is a transcription factor that regulates both the immune and non-immune components in human health and diseases.
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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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Culpepper, Courtney D., Alexandra V. Tremblay, Zhen Bian, Shuo Niu, and Yuan Liu. "IL-17A induced hematopoietic reprogramming produces both PMN and MDSC at the post-acute stage of inflammation." Journal of Immunology 200, no. 1_Supplement (May 1, 2018): 42.24. http://dx.doi.org/10.4049/jimmunol.200.supp.42.24.
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Abstract Our previous study suggests that polymorphonuclear leukocyte (PMN) response is enhanced at the post-acute stage of murine colitis due to changes in bone marrow (BM) myelopoiesis. Herein, we report that hematopoietic reprogramming during the post-acute phase of inflammation produces myeloid derived suppressor cells (MDSC) that co-infiltrate the intestine with PMN. Employing Percoll density gradients, we analyzed dynamic changes to the myeloid compartment by separating BM leukocytes from DSS colitis-to-recovery mice into four density-increasing bands with myeloid leukocytes enriched in bands III (50–60%) and IV (60–70%). Band III was comprised of monocytes and low-density granulocytes; both confirmed to be M-MDSCs and G-MDSCs, respectively, by displaying potent inhibition of T-cell proliferation. Despite significant decreases in the PMN population, presumably caused by mobilization into inflamed tissues, MDSC numbers significantly increase beginning at the post-acute stage of colitis. Furthermore, MDSC numbers do not return to baseline until late in the recovery stage. The expanded G-MDSCs also showed increased CXCR2 expression, which guides egress out of BM, and produced ROS upon PMA activation. Adoptive transfer assays demonstrated that functionally enhanced PMN infiltrated the intestine at the post-acute stage to clear the existing inflammatory reaction, while MDSC accumulated in the intestine during recovery suggesting a role in tissue repair. IL-17A signaling at the post-acute stage of inflammation likely induced hematopoietic reprogramming of the myeloid compartment, as its neutralization blocked expansion and infiltration of both PMN and MDSC.
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Fu, Shuyu, Sima Patel, Jerome Mastio, George A. Dominguez, Kevin Alicea Torres, Yulia Nefedova, Jie Zhou, and Dmitry I. Gabrilovich. "Dynamics of migration patterns of polymorphonuclear myeloid-derived suppressor cells during tumor progression." Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 137.4. http://dx.doi.org/10.4049/jimmunol.202.supp.137.4.
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Abstract Although recruitment of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) to the tumor site is well documented, little is known about their migration patterns within bone marrow in tumor progression. We found that the activation of neutrophils migration in cancer is a two-phase process. The first phase was characterized by the accumulation of a previously uncharacterized population of neutrophils that lack immunosuppressive activity but display a potent ability to spontaneously migrate, whereas the later phase is associated with accumulation of neutrophils with typical features of PMN-MDSC with low migratory activity in the bone marrow of mice with various subcutaneous (ectopic) tumors and in mice with advanced orthotopic lung cancer. Mechanistically, PM-LCs displayed increased metabolic flux through oxidative phosphorylation and glycolysis and have more ATP than that of control neutrophils. However, PMN-MDSC were indistinguishable from neutrophils from tumor-free mice in their metabolic activity. In line with studies of mice, CD15+ neutrophils exhibited greater spontaneous migration than that of PMN-MDSCs from the same patient with cancer. These results elucidate the dynamic changes that neutrophils undergo in cancer.
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Guo, Christina, Jan Rekowski, Mateus Crespo, Bora Gurel, Wei Yuan, Adam Sharp, Rafael Grochot, et al. "Abstract 3415: The neutrophil-to-lymphocyte ratio (NLR) reflects intratumor myeloid derived suppressor cell (MDSC) infiltration in metastatic castration-resistant prostate cancers (mCRPC)." Cancer Research 82, no. 12_Supplement (June 15, 2022): 3415. http://dx.doi.org/10.1158/1538-7445.am2022-3415.
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Abstract Background: High neutrophil-to-lymphocyte ratio (NLR) associates with worse overall survival (OS) from prostate cancer (PC) and low response rates to abiraterone and taxane chemotherapy and may reflect systemic inflammatory changes. A direct link between high NLR and intratumoral myeloid infiltration has not been demonstrated to date. We evaluated the relationship between NLR and intratumor immune cell densities in mCRPC biopsies. Design: mCRPC biopsies from 71 patients treated at The Institute of Cancer Research/Royal Marsden Hospital (ICR/RMH, UK) were stained by immunofluorescence for CD11b, CD15, and DAPI and by immunohistochemistry for CD3 to algorithmically quantify PMN-MDSC and T cell densities in the tumor and stromal compartments. NLR (neutrophil count divided by lymphocyte count), ALP, LDH, and albumin were obtained from blood collected contemporaneous with mCRPC biopsies. Clinical data were retrospectively collected. Negative binomial regression determined the association between leucocyte densities and log-transformed NLR. Modified Poisson regression estimated the risk ratio (RR) for the presence of PMN-MDSCs in relation to higher NLR (>3). OS was analysed using Cox regression and Kaplan-Meier. RNAseq data from Stand Up 2 Cancer/Prostate Cancer Foundation (SU2C/PCF, n=159) and RMH cohorts (n=98) were analysed by Spearman’s correlation. Results: NLR positively associated with the density of PMN-MDSCs infiltrating the tumor (p=0.0004) and stromal (p=0.0007) compartments of mCRPC biopsies as determined by Halo࣪ computational modelling. Tumors with high NLR were more likely to be infiltrated by PMN-MDSCs (RR: 1.41; 95% confidence interval [CI]: 1.04-1.92; p=0.03). NLR independently associated with worse OS from the time of mCRPC biopsy after adjusting for LDH, ALP, metastasis at the time of diagnosis, and albumin (HR: 1.71; 95% CI: 1.20-2.46). Patients with low NLR and an absence of tumor-infiltrating PMN-MDSC had longer OS than those with a high NLR, tumor-infiltrating PMN-MDSCs or a combination of both (p=0.015). Whilst there was no association between NLR or PMN-MDSC density and CD3 T cell density, RNAseq analyses of two independent CRPC cohorts showed that MDSC signatures strongly and positively associated with signatures of T cell terminal exhaustion (SU2C/PCF: rs=0.74; p<1x10-6; RMH: rs=0.64; p<1x10-6) providing credence for the impact of MDSCs on T effector function. Conclusion: Peripheral blood NLR was positively correlated with prostate tumor-infiltrating PMN-MDSC density supporting the interaction between the circulating myeloid compartment and intratumoral myeloid infiltration in patients with advanced PC. Citation Format: Christina Guo, Jan Rekowski, Mateus Crespo, Bora Gurel, Wei Yuan, Adam Sharp, Rafael Grochot, Khobe Chandran, Semini Sumanasuriya, Ana Ferreira, Andrea Alimonti, Johann S. de Bono. The neutrophil-to-lymphocyte ratio (NLR) reflects intratumor myeloid derived suppressor cell (MDSC) infiltration in metastatic castration-resistant prostate cancers (mCRPC) [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 3415.
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Wu, Sheng-Yan, and Chi-Shiun Chiang. "Distinct Role of CD11b+Ly6G−Ly6C− Myeloid-Derived Cells on the Progression of the Primary Tumor and Therapy-Associated Recurrent Brain Tumor." Cells 9, no. 1 (December 24, 2019): 51. http://dx.doi.org/10.3390/cells9010051.
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Myeloid-derived cells have been implicated as playing essential roles in cancer therapy, particularly in cancer immunotherapy. Most studies have focused on either CD11b+Ly6G+Ly6C+ granulocytic or polymorphonuclear myeloid-derived suppressor cells (G-MDSCs or PMN-MDSCs) or CD11b+Ly6G−Ly6C+ monocytic MDSCs (M-MDSCs), for which clear roles have been established. On the other hand, CD11b+Ly6G−Ly6C− myeloid-derived cells (MDCs) have been less well studied. Here, the CD11b-diphtheria toxin receptor (CD11b-DTR) transgenic mouse model was used to evaluate the role of CD11b+ myeloid-derived cells in chemotherapy for an orthotopic murine astrocytoma, ALTS1C1. Using this transgenic mouse model, two injections of diphtheria toxin (DT) could effectively deplete CD11b+Ly6G−Ly6C− MDCs while leaving CD11b+Ly6G+Ly6C+ PMN-MDSCs and CD11b+Ly6G−Ly6C+ M-MDSCs intact. Depletion of CD11b+Ly6G−Ly6C− MDCs in mice bearing ALTS1C1-tk tumors and receiving ganciclovir (GCV) prolonged the mean survival time for mice from 30.7 to 37.8 days, but not the controls, while the effectiveness of temozolomide was enhanced. Mechanistically, depletion of CD11b+Ly6G−Ly6C− MDCs blunted therapy-induced increases in tumor-associated macrophages (TAMs) and compromised therapy-elicited angiogenesis. Collectively, our findings suggest that CD11b+Ly6G−Ly6C− MDCs could be manipulated to enhance the efficacy of chemotherapy for brain tumors. However, our study also cautions that the timing of any MDC manipulation may be critical to achieve the best therapeutic result.
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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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Kim, Yun-Sun, Yeon-Jeong Kim, Eun-Kyung Kim, Jung-Mi Lee, Jeong-Hwan Seo, Young-Jun Park, Ho-Woong Kang, and Chang-Yuil Kang. "Phenotypical and functional changes in myeloid-derived suppressor cells during the tumor progression: FKBP51 regulates the suppressive function of MDSCs (66.25)." Journal of Immunology 186, no. 1_Supplement (April 1, 2011): 66.25. http://dx.doi.org/10.4049/jimmunol.186.supp.66.25.
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Abstract Immature myeloid cells which are increased by tumor-derived factors actively suppress immune cells. Therefore, they are called as myeloid-derived suppressor cells (MDSCs). Since the effect of cancer immunotherapy would be enhanced by removing MDSCs or inhibiting their suppressive function, we tried to find a target for MDSC regulation. MDSCs were increased during the tumor progression and MDSCs of late stage tumor bearing mice had stronger suppressive activity than those of early stage tumor bearing mice, in T cell proliferation assays. To find factors that change the MDSCs during the tumor progression, we analyzed gene expression profiles in MDSCs at various tumor stages and found that expression of Fkbp5 was increased in the Mo- and PMN- MDSCs of late stage tumor bearing mice. By means of rapamycin, which inhibit the PPIase function of FKBP51 protein, we demonstrate that the FKBP51 was involved in the suppressive function of MDSCs via regulation of iNOS expression. In addition, the FKBP51 enhanced the survival of MDSCs. By targeting the FKBP51, we may regulate the suppressive function of MDSCs and enhance the effect of anti-cancer immunotherapy.
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Giese, Morgan A., Laurel E. Hind, and Anna Huttenlocher. "Neutrophil plasticity in the tumor microenvironment." Blood 133, no. 20 (May 16, 2019): 2159–67. http://dx.doi.org/10.1182/blood-2018-11-844548.
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Abstract Neutrophils act as the body’s first line of defense against infection and respond to diverse inflammatory cues, including cancer. Neutrophils display plasticity, with the ability to adapt their function in different inflammatory contexts. In the tumor microenvironment, neutrophils have varied functions and have been classified using different terms, including N1/N2 neutrophils, tumor-associated neutrophils, and polymorphonuclear neutrophil myeloid–derived suppressor cells (PMN-MDSCs). These populations of neutrophils are primarily defined by their functional phenotype, because few specific cell surface markers have been identified. In this review, we will discuss neutrophil polarization and plasticity and the function of proinflammatory/anti-inflammatory and protumor/antitumor neutrophils in the tumor microenvironment. We will also discuss how neutrophils with the ability to suppress T-cell activation, referred to by some as PMN-MDSCs, fit into this paradigm.
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Ryou, Jeong-Hyun, Gwanghee Lee, Tadatsugu Taniguchi, Hideyuki Yanai, and Sho Hangai. "Abstract 242: TCTP is a target for cancer immunotherapy modulating myeloid-derived suppressor cells." Cancer Research 82, no. 12_Supplement (June 15, 2022): 242. http://dx.doi.org/10.1158/1538-7445.am2022-242.
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Abstract Myeloid-derived suppressor cells (MDSCs) are a heterogenous group of myeloid cells that are highly suppressive to antitumor lymphocyte function and trafficking to the tumor. The accumulation of MDSCs in the tumor immune microenvironment (TIME) makes immunosuppressive TIME and progressive tumor. In fact, despite notable clinical outcomes in cancer immunotherapy, many patients are refractory or relapsed to immune checkpoint inhibitor therapy, wherein obstacles imposed by TIME contribute to a great extent. Here, we show that translationally controlled tumor protein (TCTP) released by dying tumor cells is an immunomodulator crucial to full-blown MDSC accumulation in the TIME in mouse models. We provide evidence that extracellular TCTP mediates recruitment of the polymorphonuclear MDSC (PMN-MDSC) population in the TIME, which is Toll-like receptor-2 (TLR2) dependent. For human translation, we confirmed that human TCTP binds directly to human TLR2 extracellular domain and stimulates human PBMC to produce multiple cytokines. To explore therapeutic applicability, we generated anti-TCTP antibodies for TCTP inhibition. The antibodies successfully neutralized TCTP in molecular and cellular level. The antibodies also suppressed PMN-MDSC accumulation and tumor growth. The combination of anti-TCTP antibody and immune checkpoint inhibitor showed synergistic effect on tumor growth inhibition. In conclusion, extracellular TCTP is an immunomodulator recruiting PMN-MDSCs to TIME. When TCTP is removed or neutralized, PMN-MDSC counts in TIME decreased. Anti-TCTP therapy may offer a new immunotherapy strategy. Citation Format: Jeong-Hyun Ryou, Gwanghee Lee, Tadatsugu Taniguchi, Hideyuki Yanai, Sho Hangai. TCTP is a target for cancer immunotherapy modulating myeloid-derived suppressor cells [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 242.
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Jeong, Seong Mun, and Yeon-Jeong Kim. "Astaxanthin Treatment Induces Maturation and Functional Change of Myeloid-Derived Suppressor Cells in Tumor-Bearing Mice." Antioxidants 9, no. 4 (April 23, 2020): 350. http://dx.doi.org/10.3390/antiox9040350.
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Myeloid-derived suppressor cells (MDSCs) are immature myeloid cells which accumulate in stress conditions such as infection and tumor. Astaxanthin (ATX) is a well-known antioxidant agent and has a little toxicity. It has been reported that ATX treatment induces antitumor effects via regulation of cell signaling pathways, including nuclear factor erythroid-derived 2-related factor 2 (Nrf2) signaling. In the present study, we hypothesized that treatment with ATX might induce maturation of MDSCs and modulate their immunosuppressive activity. Both in vivo and in vitro treatment with ATX resulted in up-regulation of surface markers such as CD80, MHC class II, and CD11c on both polymorphonuclear (PMN)-MDSCs and mononuclear (Mo)-MDSCs. Expression levels of functional mediators involved in immune suppression were significantly reduced, whereas mRNA levels of Nrf2 target genes were increased in ATX-treated MDSCs. In addition, ATX was found to have antioxidant activity reducing reactive oxygen species level in MDSCs. Finally, ATX-treated MDSCs were immunogenic enough to induce cytotoxic T lymphocyte response and contributed to the inhibition of tumor growth. This demonstrates the role of ATX as a regulator of the immunosuppressive tumor environment through induction of differentiation and functional conversion of MDSCs.
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Takano, Tomohiro, Takayuki Matsumura, Yu Adachi, Kazutaka Terahara, Saya Moriyama, Taishi Onodera, Ayae Nishiyama, et al. "Myeloid cell dynamics correlating with clinical outcomes of severe COVID-19 in Japan." International Immunology 33, no. 4 (February 4, 2021): 241–47. http://dx.doi.org/10.1093/intimm/dxab005.
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Abstract Abstract An expanded myeloid cell compartment is a hallmark of severe coronavirus disease 2019 (COVID-19). However, data regarding myeloid cell expansion have been collected in Europe, where the mortality rate by COVID-19 is greater than those in other regions including Japan. Thus, characteristics of COVID-19-induced myeloid cell subsets remain largely unknown in the regions with low mortality rates. Here, we analyzed cellular dynamics of myeloid-derived suppressor cell (MDSC) subsets and examined whether any of them correlate with disease severity and prognosis, using blood samples from Japanese COVID-19 patients. We observed that polymorphonuclear (PMN)-MDSCs, but not other MDSC subsets, transiently expanded in severe cases but not in mild or moderate cases. Contrary to previous studies in Europe, this subset selectively expanded in survivors of severe cases and subsided before discharge, but such transient expansion was not observed in non-survivors in Japanese cohort. Analysis of plasma cytokine/chemokine levels revealed positive correlation of PMN-MDSC frequencies with IL-8 levels, indicating the involvement of IL-8 on recruitment of PMN-MDSCs to peripheral blood following the onset of severe COVID-19. Our data indicate that transient expansion of the PMN-MDSC subset results in improved clinical outcome. Thus, this myeloid cell subset may be a predictor of prognosis in cases of severe COVID-19 in Japan.
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Ito, Atsushi, Yuichi Akama, Naoko Satoh-Takayama, Kanako Saito, Takuma Kato, Eiji Kawamoto, Arong Gaowa, Eun Jeong Park, Motoshi Takao, and Motomu Shimaoka. "Possible Metastatic Stage-Dependent ILC2 Activation Induces Differential Functions of MDSCs through IL-13/IL-13Rα1 Signaling during the Progression of Breast Cancer Lung Metastasis." Cancers 14, no. 13 (July 4, 2022): 3267. http://dx.doi.org/10.3390/cancers14133267.
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Breast cancer is the most common cancer in women worldwide, and lung metastasis is one of the most frequent distant metastases. When breast cancer metastasizes to the lung, group 2 innate lymphoid cells (ILC2s) are thought to promote tumor growth via the activation of myeloid-derived suppressor cells (MDSCs), which are known to negatively regulate anticancer immune responses. However, it remains to be elucidated exactly how this ILC2–MDSC interaction is involved in tumor growth during metastases formation. Using a 4T1/LM4 breast cancer mouse model, we found that ILC2s were activated in both the micro- and macrometastatic regions, suggesting sustained activation throughout the metastatic cascades via IL-33/ST2 signaling. Consistent with IL-13 secretion from activated ILC2s, the frequencies of polymorphonuclear (PMN)- and monocytic (M)-MDSCs were also significantly elevated during the progression from micro- to macrometastatic cancer. However, the effects of ILC2-induced MDSC functionality on the microenvironment differed in a metastatic-stage-specific manner. Our findings indicate that ILC2s may induce the immunosuppressive functions of MDSCs during the later stages of metastasis. Concomitantly, ILC2 may instigate extracellular matrix remodeling by PMN-MDSC activation during the early stages of metastasis. These metastatic-stage-specific changes may contribute to metastatic tumor growth in the microenvironment of breast cancer lung metastasis.
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Aggen, David Henry, Ali Ghasemzadeh, Wendy Mao, Nivi Chowdhury, Matthew Chaimowitz, Jessica Hawley, Vinson Wang, et al. "Preclinical development of combination therapy targeting the dominant cytokine interleukin-1β for renal cell carcinoma." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): e14237-e14237. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.e14237.
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e14237 Background: Targeting myeloid-derived suppressor cells (MDSCs), key mediators of intrinsic and adaptive immune resistance, remains a significant challenge in kidney cancer immunotherapy. One potential driver of MDSC mediated tumor immunosuppression is the cytokine interleukin-1 beta (IL-1β). Although large cancer prevention studies show that targeting IL1 decreases cancer risk, the exact mechanism of anti-IL-1 mediated anti-tumor efficacy is not yet defined. To understand the immunogenic effects of IL-1β blockade and effects on MDSCs, we used the RENCA model of RCC. Methods: We inoculated BALB/c mice with 1x106 RENCA cells. On Day +10 we treated mice (n = 8/group) with vehicle, αPD1, αIL1β, cabozantinib, combination αPD1/αIL1β, or cabozantinib/αIL1β. We harvested day +18 tumors to quantify tumor size and immune cells by flow cytometry. We then isolated immune cells for differential gene expression profiling by RNAseq. Results: Treatment with αIL1β significantly decreased tumor size compared to vehicle or αPD1 monotherapy. Combining αPD1/αIL1β or cabozantinib/αIL1β potentiated the anti-tumor effects of αPD1 or cabozantinib monotherapy respectively. Anti-IL1β therapy decreased polymorphonuclear (PMN)-MDSC infiltration (αIL1β: 0.76% +/- 0.21 vs. vehicle: 1.89% +/- 0.37, P = 0.014). Relative to PD1 monotherapy, combining αPD1 and αIL1β decreased PMN-MDSCs (αPD1: 2.14% +/- 0.56 vs αPD1/αIL1β: 0.91% +/- 0.15, P = 0.033) and increased M1-like tumor associated macrophages (TAM) (αPD1: 0.798% +/- 0.21 vs. αPD1/αIL1β: 12.04% +/- 2.9, P = 0.0008). Gene expression profiling from sorted immune cells from αIL1β treated tumors revealed multiple differentially regulated cytokines including interleukin-6, IFN-γ, and IL-10. Conclusions: Blockade of IL-1β depletes intratumoral PMN-MDSCs and increases M1-like TAM with minimal effects observed on the T cell compartment. Treatment with cabozantinib or αPD1 in combination with αIL1β led to sustained control of tumor growth. IL-1β represents a promising target for kidney cancer immunotherapy. Based on the preclinical data, a clinical trial of neoadjuvant αPD1 and αIL1β therapy is planned for patients with high risk RCC.
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Zhou, Jingying, Man Liu, Hanyong Sun, Yu Feng, Liangliang Xu, Anthony W. H. Chan, Joanna H. Tong, et al. "Hepatoma-intrinsic CCRK inhibition diminishes myeloid-derived suppressor cell immunosuppression and enhances immune-checkpoint blockade efficacy." Gut 67, no. 5 (September 22, 2017): 931–44. http://dx.doi.org/10.1136/gutjnl-2017-314032.
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ObjectiveMyeloid-derived suppressor cells (MDSCs) contribute to tumour immunosuppressive microenvironment and immune-checkpoint blockade resistance. Emerging evidence highlights the pivotal functions of cyclin-dependent kinases (CDKs) in tumour immunity. Here we elucidated the role of tumour-intrinsic CDK20, or cell cycle-related kinase (CCRK) on immunosuppression in hepatocellular carcinoma (HCC).DesignImmunosuppression of MDSCs derived from patients with HCC and relationship with CCRK were determined by flow cytometry, expression analyses and co-culture systems. Mechanistic studies were also conducted in liver-specific CCRK-inducible transgenic (TG) mice and Hepa1–6 orthotopic HCC models using CRISPR/Cas9-mediated Ccrk depletion and liver-targeted nanoparticles for interleukin (IL) 6 trapping. Tumorigenicity and immunophenotype were assessed on single or combined antiprogrammed death-1-ligand 1 (PD-L1) therapy.ResultsTumour-infiltrating CD11b+CD33+HLA-DR− MDSCs from patients with HCC potently inhibited autologous CD8+T cell proliferation. Concordant overexpression of CCRK and MDSC markers (CD11b/CD33) positively correlated with poorer survival rates. Hepatocellular CCRK stimulated immunosuppressive CD11b+CD33+HLA-DR− MDSC expansion from human peripheral blood mononuclear cells through upregulating IL-6. Mechanistically, CCRK activated nuclear factor-κB (NF-κB) via enhancer of zeste homolog 2 (EZH2) and facilitated NF-κB-EZH2 co-binding to IL-6 promoter. Hepatic CCRK induction in TG mice activated the EZH2/NF-κB/IL-6 cascade, leading to accumulation of polymorphonuclear (PMN) MDSCs with potent T cell suppressive activity. In contrast, inhibiting tumorous Ccrk or hepatic IL-6 increased interferon γ+tumour necrosis factor-α+CD8+ T cell infiltration and impaired tumorigenicity, which was rescued by restoring PMN-MDSCs. Notably, tumorous Ccrk depletion upregulated PD-L1 expression and increased intratumorous CD8+ T cells, thus enhancing PD-L1 blockade efficacy to eradicate HCC.ConclusionOur results delineate an immunosuppressive mechanism of the hepatoma-intrinsic CCRK signalling and highlight an overexpressed kinase target whose inhibition might empower HCC immunotherapy.
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Alcantara, Marice, Dayson Moreira, Chia-Yang Hung, Dongfang Wang, JoAnn Hsu, Sumanta Pal, and Marcin Kortylewski. "541 Investigating myeloid derived suppressor cells (MDSCs) and oligonucleotide based targeting of STAT3 in renal cell carcinoma." Journal for ImmunoTherapy of Cancer 8, Suppl 3 (November 2020): A577. http://dx.doi.org/10.1136/jitc-2020-sitc2020.0541.
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BackgroundRecent advancements in the treatment of renal cell carcinoma (RCC) using immune checkpoint inhibitors (ICI) against PD1 or CTLA-4 receptors have improved survival rates in patients. However, more than half of RCC patients does not respond to anti-PD-1/-CTLA-4 combination immunotherapy. Thus, we decided to investigate mechanisms underpinning the resistance to ICI at the cellular and molecular levels.MethodsWe utilized multicolour flow cytometry and Luminex assays to investigate patient peripheral blood and used syngeneic mouse models to determine the efficacy of oligonucleotide based targeting of STAT3ResultsFirst, we characterized immunosuppressive myeloid cell populations, T cell subsets and immune biomarkers in blood samples from RCC patients with advanced stage IV disease, undergoing anti-PD-1/-CTLA-4 (nivolumab/ipilimumab) combination therapy. Results of our multicolor flow cytometry and plasma analysis suggested that ICI therapy is associated with a significant almost 15-fold increase of polymorphonuclear MDSCs (PMN-MDSCs) in the peripheral blood of RCC patients over the course of 3 therapeutic cycles. Notably, we found that PMN-MDSCs showed high levels of activated Signal Transducer and Activator of Transcription 3 (pSTAT3) and a significant increase its downstream target Arginase-I between cycle 1 and cycle 8 of treatment (P=0.0008). The pSTAT3/ARG-1 signaling is known for promoting tumor immune evasion, thus strongly suggesting that immature PMN-MDSCs are potentially involved in limiting outcome of ICI therapy in RCC patients similar as shown before in other genitourinary cancers such as prostate and bladder cancers. We recently developed a strategy to target STAT3 selectively in tumor-associated myeloid cells using using STAT3 antisense oligonucleotide (STAT3ASO) conjugated to immunostimulatory CpG oligodeoxynucleotides acting as targeting moiety. In our initial efficacy studies, we assessed activity of three versions of CpG-STAT3ASO conjugates with various chemical modifications, such as 2’-O’methyl- or locked nucleic acid, in a syngeneic bladder tumor model (MB49). MB49 cancer cells were subcutaneously injected into two flanks of male C57BL/6 mice and treated every second day with 5 mg/kg of various CpG-STAT3ASO injected intratumorally into one of the tumor sites. All CpG-STAT3ASOs inhibited tumor cell growth in both treated and distant tumors in comparison to controls. The immunohistochemical analysis indicated an increase in the percentage of CD8+ T cell with reduction of regulatory T cells within CpG-STAT3ASO treated tumors in comparison to controls, suggesting activation of CD8 T cell-mediated antitumor immunity.ConclusionsOverall, our preliminary results suggest that immune suppressive pSTAT3+/ARG-1+ PMN-MDSCs accumulate in patients with RCC undergoing ICI combination therapy, which may potentially contribute to resistance to ICIs. Targeting STAT3 signaling in the RCC-associated myeloid cells using CpG-STAT3ASO may provide a potential novel strategy for augmenting immune checkpoint therapies.
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Li, Tianyu, Xinyu Zhang, Zhuo Lv, Li Gao, and Huimin Yan. "Increased Expression of Myeloid-Derived Suppressor Cells in Patients with HBV-Related Hepatocellular Carcinoma." BioMed Research International 2020 (March 14, 2020): 1–8. http://dx.doi.org/10.1155/2020/6527192.
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Background and Aim. Myeloid-derived suppressor cells (MDSCs) have attracted attention due to their important role in tumor immune escape. Several studies have investigated the involvement of MDSCs into hepatocellular carcinoma (HCC); however, due to the difference of MDSC phenotype, patient types, and sample source among the studies, the results were inconsistent and controversial. The present study aimed to confirm the expression and clinical significance of MDSCs in HBV-related HCC patients. Methods. The percentages of MDSCs, IFN-γ-producing CD4 and CD8 T cells in the peripheral blood of HCC patients, chronic hepatitis B (CHB) patients, and healthy controls (HC) were determined by flow cytometry. The serum concentrations of IL-10 and TNF-α were determined by ELISA. The association of the percentages of MDSCs with tumor burden, liver function parameters, systemic inflammation-related indexes, and IFN-γ-producing T cells was assessed. Results. The percentages of MDSCs and PMN-MDSCs were significantly higher in HCC patients than those in CHB patients and HC. The level of MDSCs was correlated with indirect bilirubin and prealbumin, as well as systemic inflammation response index, monocyte/lymphocyte ratio, and monocyte counts. The frequency of IFN-γ-producing CD8 T cells of HCC patients was lower than that of HC. However, there was no relationship between MDSCs and IFN-γ-producing CD8 T cells. The level of IL-10 in HCC patients was significantly higher than that in CHB patients. Conclusion. MDSCs seem to play an important role in the process leading from chronic HBV infection to HCC. Early inhibiting these cells could affect tumor progression.
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Khan, Hamza, Anas Awan, Maria Shishikura, Carley Blevins, Kristen Rodgers, Yuping Mei, Wasay Nizam, et al. "Abstract 271: Monitoring of CCR2 and CCR5 expression on circulating myeloid derived suppressor cells (MDSCs) in non-small cell lung cancer as a correlate of minimum residual disease." Cancer Research 82, no. 12_Supplement (June 15, 2022): 271. http://dx.doi.org/10.1158/1538-7445.am2022-271.
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Abstract Objectives: Myeloid derived suppressor cells (MDSCs) are immature cells that aid in cancer progression and dissemination via immune system suppression. Previous work has shown that CCR 2 (C-C chemokine receptor) and CCR 5 expression on MDSCs is increased in non-small cell lung cancer (NSCLC). We hypothesized that patients with lung cancer will have detectable peripheral MDSCs with CCR2 and CCR5 expression preoperatively, that it would decrease immediately postoperatively, and then increase longitudinally if tumor recurs. Materials & Methods: As part of a prospective longitudinal study, whole blood samples were obtained from patients suspected to have primary lung cancer prior to surgery. Patients were excluded if they were minors, could not provider consent, had malignancy within the past 10 years or any immunosuppressive condition. Blood samples were obtained prior to surgery or at follow-up in clinic and processed within 1 hour of acquisition. We stained samples via 2 different methods: 1) whole blood and 2) peripheral blood mononuclear cells (PBMC) extracted from Ficoll density gradient and determined that whole blood staining had superior results. Samples were analyzed via flow cytometer and gated after defining MO (monocytic)-MDSCs as CD33+HLADRlow/-CD14+ and PMN-MDSCs as CD33+HLADR-CD15+. MDSCs were reported as a percentage of live leukocytes and means were reported with T-test performed for statistical analysis. Results: A total of 18 patients were recruited with a median age of 69 years (63.8-75) and 61% (11/18) females. Adenocarcinoma was present in 16, carcinoid tumor in 1 and both adenocarcinoma and carcinoid tumor in 1 patient. Stage I and Stage II were the most common (66.7% and 22.2%, respectively). Majority of the tumors were in the right upper lobe (55.6%). There were 7 healthy controls with a median age of 29 years (28-43) and 71% females. There was a significantly increased proportion of MO-MDSCs in NSCLC patients preoperatively compared to healthy controls (11.64% versus 5.02%, p = 0.02). CCR2+CCR5+ MO-MDSCs were 0.85% in patients versus 0.06% in controls (p=0.04). No differences were noted with PMN-MDSCs. Five patients had post-operative follow up (mean 152 days) with an average decrease of 63% in MO-MDSCs, 68% in CCR2+CCR5+ MO-MDSCs and no recurrence of tumor on CT scans. Conclusion: Early results of this on-going study demonstrate the detection of circulating CCR2+CCR5+ MO-MDSCs in the preoperative whole blood of NSCLC patients compared to healthy controls. Resection of the tumor is associated with a decrease of these MO-MDSCs after treatment. We are evaluating if any increase in CCR2+CCR5+ MO-MDSC in long term will allow us to use it as an adjuvant tool along with CT monitoring as a biomarker of residual or recurrent disease. Citation Format: Hamza Khan, Anas Awan, Maria Shishikura, Carley Blevins, Kristen Rodgers, Yuping Mei, Wasay Nizam, Shun Ishiyama, Yun Chen, Richard Battafarano, Errol Bush, Stephen Broderick, Stephen Yang, Hajime Orita, Peng Huang, Ada Tam, Jinny Ha, Franck Housseau, Malcolm Brock. Monitoring of CCR2 and CCR5 expression on circulating myeloid derived suppressor cells (MDSCs) in non-small cell lung cancer as a correlate of minimum residual disease [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 271.
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Andrés, Celia María Curieses, José Manuel Pérez de la Lastra, Celia Andrés Juan, Francisco J. Plou, and Eduardo Pérez-Lebeña. "Myeloid-Derived Suppressor Cells in Cancer and COVID-19 as Associated with Oxidative Stress." Vaccines 11, no. 2 (January 19, 2023): 218. http://dx.doi.org/10.3390/vaccines11020218.
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Myeloid-derived suppressor cells MDSCs are a heterogeneous population of cells that expand beyond their physiological regulation during pathologies such as cancer, inflammation, bacterial, and viral infections. Their key feature is their remarkable ability to suppress T cell and natural killer NK cell responses. Certain risk factors for severe COVID-19 disease, such as obesity and diabetes, are associated with oxidative stress. The resulting inflammation and oxidative stress can negatively impact the host. Similarly, cancer cells exhibit a sustained increase in intrinsic ROS generation that maintains the oncogenic phenotype and drives tumor progression. By disrupting endoplasmic reticulum calcium channels, intracellular ROS accumulation can disrupt protein folding and ultimately lead to proteostasis failure. In cancer and COVID-19, MDSCs consist of the same two subtypes (PMN-MSDC and M-MDSC). While the main role of polymorphonuclear MDSCs is to dampen the response of T cells and NK killer cells, they also produce reactive oxygen species ROS and reactive nitrogen species RNS. We here review the origin of MDSCs, their expansion mechanisms, and their suppressive functions in the context of cancer and COVID-19 associated with the presence of superoxide anion •O2− and reactive oxygen species ROS.
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Bianchi, Anna, Iago De Castro Silva, Nilesh U. Deshpande, Siddharth Mehra, Vanessa T. Garrido, Samara Singh, Christine I. Rafie, et al. "Abstract C033: KRAS-TP53 cooperativity regulates Cxcl1 to sustain tumor-permissive circuitry via granulocyte-derived CXCR2-TNF signaling in pancreatic cancer." Cancer Research 82, no. 22_Supplement (November 15, 2022): C033. http://dx.doi.org/10.1158/1538-7445.panca22-c033.
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Abstract Objective: We have recently shown that KRAS-TP53 genomic co-alteration is associated with innate immune-enriched and T-cell-excluded tumor microenvironments (TME), chemotherapy resistance, and poor survival in pancreatic ductal adenocarcinoma (PDAC) patients. We sought to define the multi-cellular crosstalk that underlies these effects by dissecting how cancer cell-autonomous transcriptional programs orchestrate tolerogenic circuitries to mediate chemoresistance in KRAS-TP53 cooperative PDAC. Methods: Spatial neighborhood analysis via Imaging Mass Cytometry (IMC) was performed in patient-derived PDAC sections. Immune profiling and bulk RNA-seq in whole tumors, as well as bulk-RNAseq in intratumoral F4/80-Ly6Ghi neutrophilic(PMN)-MDSCs in orthotopic KPC tumors with/without CRISPR/Cas9 editing of Cxcl1 was performed. Effect of TNFR2 inhibition via etanercept on ex vivo co-cultures of intratumoral PMN-MDSC with KPC tumor cells/CAFs and T-cells, as well as in orthotopic KPC models in vivo with/without gemcitabine+paclitaxel chemotherapy was performed. Results: Interrogation of cancer cell transcriptomes and IMC architecture in human tumors reveals disproportionate enrichment of Cxcl1 in KRAS-TP53 co-altered PDAC. IMC-enabled spatial neighborhood analysis in KRAS-TP53 co-altered human PDAC TMEs demonstrates strong spatial contiguity between PanCK+CXCL1+ tumor islands and cognate CD15+CXCR2+ PMN-MDSCs, with exclusion of CD8+ T-cells from tumor cell:PMN-MDSC communities. In murine orthotopic models that phenocopy T-cell excluded human PDAC, genetic silencing of tumor cell-intrinsic Cxcl1 overcomes CD8+ T-cell exclusion and controls tumor growth in a CD8+ T-cell dependent manner in vivo. Transcriptomes from KPC-Cxcl1KO tumors not only reveal enrichment in pathways encoding for T-cell effector activity but also attenuation in pathways related to innate immune function. These immune potentiating effects upon Cxcl1 silencing are driven in large part by reprogramming of trafficking dynamics and immunosuppressive potential in intratumoral CXCR2+ PMN-MDSCs. To identify neutrophil-intrinsic mechanisms that govern remodeling of the TME following Cxcl1 silencing, transcriptomes in intratumoral KPC-Cxcl1KO PMN-MDSCs reveal strong downregulation of MAPK and TNF pathways, with signaling studies implicating a novel Cxcr2-Ikk-Map3k8-Tnf axis. We uncover novel effects of neutrophil-derived TNF in promoting tumor cell-Cxcl1 production, inflammatory CAF polarization, and T-cell dysfunction in ex vivo co-cultures, predominantly via a membraneTNF-TNFR2 dependent mechanism. Systemic TNFR2 inhibition via etanercept not only augments T-cell activation, but also mitigates tumor-wide Cxcl1 production, stromal inflammation, and CAF:tumor cell IL6-STAT3 signaling to improve sensitivity to gemcitabine+paclitaxel chemotherapy in vivo. Conclusion: These data uncover novel tumor-permissive/chemoresistant circuitries in which cancer cell-intrinsic Cxcl1 sustains innate immunoregulatory and tolerogenic signaling via neutrophil-derived TNF in the PDAC TME. Citation Format: Anna Bianchi, Iago De Castro Silva, Nilesh U. Deshpande, Siddharth Mehra, Vanessa T. Garrido, Samara Singh, Christine I. Rafie, Zhou Zhiqun, Ifeanyichukwu C. Ogobuiro, Austin R. Dosch, Nagaraj Nagathihalli, Nipun B. Merchant, Jashodeep Datta. KRAS-TP53 cooperativity regulates Cxcl1 to sustain tumor-permissive circuitry via granulocyte-derived CXCR2-TNF signaling in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr C033.
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Lu, Xuemin, and Xin Lu. "Enhancing immune checkpoint blockade therapy of genitourinary malignancies by co-targeting PMN-MDSCs." Biochimica et Biophysica Acta (BBA) - Reviews on Cancer 1877, no. 3 (May 2022): 188702. http://dx.doi.org/10.1016/j.bbcan.2022.188702.
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Rase, Viva Jeanne, James M. Haughian, and Nicholas A. Pullen. "The effects of a CRISPR/Cas9 IL-6 knockout in 4T1 mammary carcinoma cells on myeloid-derived suppressor cells (MDSCs) and Th17/Th22 cells." Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 135.22. http://dx.doi.org/10.4049/jimmunol.202.supp.135.22.
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Abstract The 4T1 mouse mammary carcinoma cell line is syngeneic to Balb/c mice and is an effective tumor model to study the interactions between the immune system and metastatic breast cancer. The pro-tumor effects that myeloid-derived suppressor cell (MDSC) populations have on CD8+ T cells and Tregs are well known, but comparably less attention has been directed at the relationship between MDSCs and Type III immune Th17/Th22 cells in breast cancer. MDSCs and Th17/Th22 cells have been linked in other inflammatory settings, so in this study, we investigated MDSC, Th17 and Th22 cell interactions in 4T1 tumors, and the role of tumor-derived IL-6 in these interactions. IL-6 plays a key role in the induction of MDSCs under pathological conditions, as well as fate determining in Th maturation. Thus, the removal of IL-6 from 4T1 tumors allowed us to better characterize the source of these interactions. Populations of Monocytic (M)-MDSCs (CD11b+Ly-6G−Ly-6Chi), Polymorphonuclear (PMN)-MDSCs (CD11b+Ly-6G+Ly-6Clow), Th17 (CD3+CD4+RORγt+IFN-γ−IL-17A+IL-22−) and Th22 (CD3+CD4+IFN-γ−RORγt−IL-17A−IL-22+) cells were identified in peripheral blood, spleen, tumor and bone marrow (BM) of mice bearing wild-type and IL-6 knockout 4T1 tumors. Finally, we isolated 4T1 induced MDSCs (CD11b+Gr-1+)and cocultured them with healthy donors to investigate Th17 and Th22 population expansion. Our findings provide further insight into the interactions among MDSCs, Th17 and Th22 cells in a murine cancer model, which may inform immunotherapy efficacy and outcomes in human breast cancer.
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Theivanthiran, Balamayooran, Fang Liu, Nicholas DeVito, Michael Plebanek, and Brent Hanks. "319 The tumor-intrinsic NLRP3 inflammasome establishes a pulmonary metastatic niche via type II epithelial HSP70/TLR4 signaling and facilitates disease hyperprogression in response to immunotherapy." Journal for ImmunoTherapy of Cancer 9, Suppl 2 (November 2021): A343. http://dx.doi.org/10.1136/jitc-2021-sitc2021.319.
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BackgroundOur understanding of those underlying mechanisms that contribute to metastatic progression in melanoma remains limited. While uncommon, melanoma hyperprogression in response to immunotherapy is likely to be an extreme form of acquired resistance. Therefore, studies that define the underlying mechanisms of these processes are expected to provide insight into the discovery of novel therapeutic targets and predictive biomarkers. We previously demonstrated that tumor-intrinsic NLRP3 drives adaptive resistance to anti-PD-1 immunotherapy (anti-PD-1) by inducing the recruitment of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) via the upregulation of CXCL5. Gain-of-function polymorphisms in the TLR4 gene have been associated with pulmonary metastases in melanoma patients. We have shown HSP70 to promote PMN-MDSC chemotaxis via the stimulation of TLR4 signaling. As a result, we hypothesized that the tumor NLRP3 inflammasome may also contribute to distant metastatic progression and disease hyperprogression during immunotherapy by establishing a long-distance signaling axis mediated by HSP70-TLR4 signaling in the lung.MethodsWe pharmacologically and genetically inhibited the NLRP3 inflammasome and HSP70 in a transgenic BRAFV600E mouse model to examine their role in distant metastatic progression before and during anti-PD-1. An inducible type II pulmonary epithelial cell-specific TLR4 knock-out mouse model was engineered to examine the role of distant HSP70-TLR4 signaling in the recruitment of PMN-MDSCs and subsequent metastatic progression to the lung. Plasma HSP70 levels were monitored in melanoma patients undergoing anti-PD-1ResultsAnti-PD-1 significantly increases CXCL2/CXCL5 expression and PMN-MDSC accumulation in the lungs of the transgenic BRAFV600E model. This effect is reversed by 1) tumor-targeted ablation and pharmacologic inhibition of NLRP3 but not systemic host knock-out of NLRP3, 2) Pharmacologic Wnt5a ligand inhibition, 3) tumor-specific ablation and inhibition of HSP70. Inducible knock-out of TLR4 in type II epithelial cells suppressed Wnt5a and CXCL5 expression and inhibited the recruitment of PMN-MDSCs to the lung in response to anti-PD-1. Tumor-specific inhibition of NLRP3/HSP70 and lung-specific ablation of TLR4 suppressed metastatic progression following anti-PD-1 in the BRAFV600E melanoma model. Combination anti-PD-1 and NLRP3 inhibition suppressed primary melanoma progression and distant melanoma metastases versus anti-PD-1 monotherapy. Elevated plasma levels of HSP70 were associated with disease hyperprogression in metastatic melanoma patients undergoing anti-PD-1Abstract 319 Figure 1Tumor-intrinsic NLRP3 inflammasome and metastasisConclusionsTogether, these results describe a novel cross-talk mechanism between the primary tumor and the lung that mediates distant metastatic progression that is accentuated following anti-PD-1 (figure 1). Future clinical studies are needed to evaluate the pharmacologic inhibition of this tumor-lung NLRP3/HSP70/TLR4/Wnt5a/CXCL5 axis on melanoma metastasis and disease hyperprogression during checkpoint inhibitor immunotherapy
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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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Giridharan, Thejaswini, Sora Suzuki, Tiffany R. Emmons, ANM Nazmul Khan, Michael B. Yaffe, Emese Zsiros, Kunle Odunsi, Manmeet Bhalla, Elsa Bou Ghanem, and Brahm H. Segal. "Role of the extracellular ATP/adenosine pathway in neutrophil-mediated T cell suppression in ovarian cancer microenvironment." Journal of Immunology 208, no. 1_Supplement (May 1, 2022): 177.15. http://dx.doi.org/10.4049/jimmunol.208.supp.177.15.
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Abstract The extracellular ATP (eATP)/adenosine (ADO) pathway is a key modulator of innate and adaptive immunity and is a target for immunotherapy for cancer. In the tumor microenvironment (TME) and conditions of chronic injury, ATP is released by dying cells and is hydrolyzed by the ecto-nucleotidase CD39 to AMP, and further to ADO by CD73. We previously observed that normal neutrophils (PMN) acquire a T cell suppressor phenotype mimicking PMN-MDSCs when exposed to the TME. Using a coculture system consisting of ascites supernatants (ASC) from patients with ovarian cancer (OC) as an authentic component of the TME and concentrations of healthy donor PMN and T cells that mimic those in OC ascites, we found that ASC-primed PMNs inhibit stimulated T cell proliferation, activation and metabolic responses. This suppressor activity was dependent on several PMN pathways, including complement signaling and NADPH oxidase. Since PMNs regulate and respond to signaling from the eATP/ADO pathway, we asked whether eATP/ADO mediates PMN suppressor function. PMNs had high constitutive expression of CD39 that was unaffected by ASC exposure, and inhibition of CD39 by POM-1 abrogated PMN suppressor function. CD73 inhibitor Adenosine 5′-(α,β-methylene) diphosphate also abrogated PMN suppressor function while using a different inhibitor (AB-680) had no effect. Neither ADO receptor inhibitors nor the addition of adenosine deaminase to deplete ADO affected PMN suppressor function. Together, these studies point to eATP as a modulator of PMN suppressor function in the TME and the potential to abrogate suppression by targeting CD39. Future studies will address the specific signaling functions of eATP on PMN in the TME that drive suppressor function. Supported by grant from NIH (5R01CA188900)
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Lin, Lin, Paul G. Pavicic, Patricia A. Rayman, Charles Tannenbaum, Brian I. Rini, Thomas Hamilton, James Finke, and C. Marcela Diaz-Montero. "Accumulation of tumor infiltrating myeloid-derived suppressor cells associates with changes in the immune landscape of clear cell renal cell carcinoma." Journal of Clinical Oncology 36, no. 6_suppl (February 20, 2018): 655. http://dx.doi.org/10.1200/jco.2018.36.6_suppl.655.
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655 Background: Myeloid-derived suppressor cells (MDSC) are capable of inducing profound immune suppression of anti-tumor T cell responses. Here we examined the ability of intratumoral MDSC accumulation to alter the immune landscape of RCC and to identify the factors involved. Methods: Using flow cytometry, 41 clear cell RCC nephrectomy samples were assessed for their total MDSC infiltrate and the percentage of granulocytic (PMN-MDSC) or monocytic (M-MDSC) subsets. RNA isolated from these tumor samples and 4 non-tumor samples was also evaluated for expression levels of immune-related genes using a Nanostring PanCancer immune panel. A multiple linear regression model was used to identify which immune-related genes might be significantly associated with PMN-MDSC intratumoral accumulation. Log-Rank test was used for comparison of survival curves. Results: Genes encoding cytokines, cancer-testis antigens, interleukins, and T cell function were differentially expressed by clear cell RCC and the non-tumor samples. The transcription of 55 immune-related genes was significantly associated (FDR adjusted p < 0.05) with PMN-MDSC infiltration, including mediators of MDSC recruitment such as CXCL1, CXCL3, CXCL5, CXCR2, IL8, LIF, S100A8, CSF3R, and CCR3, and molecules governing MDSC expansion and function such as IL10, C/EBPB, CD44, COX2, and NFATC3. When a statistically significant 10 gene signature was analyzed in the context of patient survival using the TCGA database of clear cell RCC patients (n = 945), a strong association between the expression of these genes and reduced survival was observed. Moreover, this association seemed to be additive, with expression of 7-10 of these genes correlating with poorer survival when compared to patients expressing 3 or less (p < 0.0001). Conclusions: Consistent with previous studies defining the immunoregulatory role of MDSCs, these results suggest that MDSC accumulation can alter the inflammatory state of the tumor, and indicate that mediators associated with the function of PMN-MDSCs can have a negative impact on outcome. Mechanistic studies aimed at identifying the functionally relevant mediators are ongoing.
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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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Alghamri, Mahmoud, Ruthvik Avvari, Rohit Thalla, Li Zhang, Maria Ventosa, Ayman Taher, Felipe Núñez, et al. "TAMI-52. G-CSF SECRETED BY EPIGENETICALLY REPROGRAMMED MUTANT IDH1 GLIOMA STEM CELLS, REVERSES THE MYELOID CELLS’-MEDIATED IMMUNOSUPPRESSIVE TUMOR MICROENVIRONMENT." Neuro-Oncology 22, Supplement_2 (November 2020): ii224. http://dx.doi.org/10.1093/neuonc/noaa215.939.
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Abstract Mutation in isocitrate dehydrogenase (mIDH) is the main genetic lesion that defines clinical glioma subtypes and prognosis. This gain of function mutation is associated with the production of the oncometabolite, R-2-hydroxyglutarate, that inhibits α-ketoglutarate dependent enzymes such as TET2 and the Jumonji-C domain containing demethylases. The resultant epigenetic modifications elicit profound effects on the tumor biology and on the glioma-infiltrating immune cells. Here, we report that in genetically engineered mouse glioma models(1), IDH1 mutation caused an expansion of tumor infiltration granulocytes. Upon phenotypic and functional characterization, we uncovered that granulocytes in mIDH1 glioma express low level of immunosuppressive molecules and did not inhibit T-cell function. Single-cell sequencing revealed that these granulocytes are heterogeneous and composed of three distinct populations; neutrophils, pre-neutrophils, and a small fraction of immunosuppressive PMN-MDSCs. Moreover, primary human gliomas showed a higher cellular fraction exhibiting the PMN-MDSCs gene signature in wtIDH1 tumors than the mIDH1 tumors. The mechanism by which mIDH1 mediates non-immune suppressive granulocytes expansion involves epigenetic reprogramming which leads to enhanced expression of granulocyte colony-stimulating factor (G-CSF) in stem-like cells. High G-CSF gene expression is correlated with favorable patient outcome solely in LGG-astrocytoma with mIDH1. Thus, G-CSF represents a potential therapeutic that can be harnessed to improve immunotherapeutic responses in wild type IDH1 glioma patients.
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Zhou, Xingyu, Deliang Fang, Haohan Liu, Xinde Ou, Chaoyue Zhang, Zirui Zhao, Shaoji Zhao, et al. "PMN-MDSCs accumulation induced by CXCL1 promotes CD8+ T cells exhaustion in gastric cancer." Cancer Letters 532 (April 2022): 215598. http://dx.doi.org/10.1016/j.canlet.2022.215598.
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Li, Bao-Hua, Wei Jiang, Shu Zhang, Na Huang, Jin Sun, Jun Yang, and Zong-Fang Li. "The spleen contributes to the increase in PMN-MDSCs in orthotopic H22 hepatoma mice." Molecular Immunology 125 (September 2020): 95–103. http://dx.doi.org/10.1016/j.molimm.2020.07.002.
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