Oxaliplatin regulates myeloid-derived suppressor cell-mediated immunosuppression via downregulation of nuclear factor-κB 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-κB signaling in MDSCs. Thus, oxaliplatin has the potential to be used as an immunoregulatory agent as well as a cytotoxic drug in cancer treatment.