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Oxaliplatin regulates myeloid-derived suppressor cell-mediated immunosuppression via downregulation of nuclear factor-?B signaling.

ABSTRACT: Myeloid-derived suppressor cells (MDSCs) represent one of the major types of immunoregulatory cells present under abnormal conditions, including cancer. These cells are characterized by their immature phenotype and suppressive effect on various immune effectors. In both human and mouse, there are two main subsets of MDSCs: polymorphonuclear (PMN)-MDSCs and mononuclear (Mo)-MDSCs. Thus, strategies to regulate MDSC-mediated immunosuppression could result in the enhancement of anticancer immune responses. Oxaliplatin, a platinum-based anticancer agent, is widely used in clinical settings. It is known to induce cell death by interfering with double-stranded DNA and interrupting its replication and transcription. In this study, we found that oxaliplatin has the potential to regulate MDSC-mediated immunosuppression in cancer. First, oxaliplatin selectively depleted MDSCs, especially Mo-MDSCs, but only minimally affected T cells. In addition, sublethal doses of oxaliplatin eliminated the immunosuppressive capacity of MDSCs and induced the differentiation of MDSCs into mature cells. Oxaliplatin treatment diminished the expression of the immunosuppressive functional mediators arginase 1 (ARG1) and NADPH oxidase 2 (NOX2) in MDSCs, while an MDSC-depleting agent, gemcitabine, did not downregulate these factors significantly. Oxaliplatin-conditioned MDSCs had no tumor-promoting activity in vivo. In addition, oxaliplatin modulated the intracellular NF-?B signaling in MDSCs. Thus, oxaliplatin has the potential to be used as an immunoregulatory agent as well as a cytotoxic drug in cancer treatment.

SUBMITTER: Kim NR

PROVIDER: S-EPMC6346236 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Oxaliplatin regulates myeloid-derived suppressor cell-mediated immunosuppression via downregulation of nuclear factor-κB signaling.

Kim Na-Rae NR Kim Yeon-Jeong YJ

Cancer medicine 20181227 1

Myeloid-derived suppressor cells (MDSCs) represent one of the major types of immunoregulatory cells present under abnormal conditions, including cancer. These cells are characterized by their immature phenotype and suppressive effect on various immune effectors. In both human and mouse, there are two main subsets of MDSCs: polymorphonuclear (PMN)-MDSCs and mononuclear (Mo)-MDSCs. Thus, strategies to regulate MDSC-mediated immunosuppression could result in the enhancement of anticancer immune res ...[more]

PMID: 30592157

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Project description:The presence of tumor infiltrating lymphocytes (TILs) is associated with a longer overall survival in advanced stage epithelial ovarian cancer. Despite the prognostic impact of TILs, response to checkpoint-inhibitors and antigen-specific active immunotherapy is limited in ovarian cancer. The goal of our study was to investigate the interaction between ovarian cancer and the innate and adaptive immune system in the ID8-fLuc syngeneic ovarian cancer mouse model. For the in vivo experiments C57BL/6, B6.129S7-Rag1tm1Mom/J, and B6.129P2(SJL)-Myd88tm1.1Defr/J mice were inoculated with ID8-fLuc. In vivo depletion experiments were performed using clodronate liposomes (CL), anti-CD8a, anti-GR1, anti-colony stimulating factor 1 (anti-CSF1), and TMβ1 (anti-CD122). Immune read out was performed by fluorescent activated cell sorting analysis for effector T cells, regulatory T cells, natural killer cells, B cells, macrophages, and myeloid derived suppressor cells (MDSC), immunohistochemistry for MDSC and tumor-associated macrophages (TAM) and immunofluorescence for M1 and M2 TAM in the vascular context. The effect of MDSC on T cell proliferation and phenotype were studied in vitro. We discovered that the absence of T and B cells did not influence tumor growth or survival of B6.129S7-Rag1tm1Mom/J mice compared to immunocompetent C57BL/6 mice. CL-induced macrophage depletion promoted tumor proliferation and shortened survival in C57BL/6 mice (p = 0.004) and in B6.129S7-Rag1tm1Mom/J mice (p = 0.0005). During CL treatment, we observed a clear increase of pro-inflammatory cytokines (p ≤ 0.02) and monocytic MDSC (p ≤ 0.01). Selective depletion of MDSC by anti-GR1 improved survival, certainly in comparison to mice treated with anti-CSF1 (p = 0.01-median survival 91 vs. 67.5 days). B6.129P2(SJL)-Myd88tm1.1Defr/J mice displayed to a longer median survival compared to C57BL/6 mice (90 vs. 76 days). MDSC activated by ID8-fLuc conditioned medium or ascites of tumor-bearing mice showed T cell suppressive functions in vitro. Based on these findings, we conclude that the adaptive immune system does not efficiently control tumor growth in the ID8-fLuc model. In addition, we discovered a prominent role for MDSC as the driver of immunosuppression in the ID8-fLuc ovarian cancer mouse model.

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Oxaliplatin regulates myeloid-derived suppressor cell-mediated immunosuppression via downregulation of nuclear factor-?B signaling.

Publications

Oxaliplatin regulates myeloid-derived suppressor cell-mediated immunosuppression via downregulation of nuclear factor-κB signaling.

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