Cisplatin inhibits frequency and suppressive activity of monocytic myeloid-derived suppressor cells in cancer patients

Abstract

Cancer immunotherapies have induced long-lasting responses in cancer patients including those with melanoma and head and neck squamous cell carcinoma (HNSCC). However, the majority of treated patients does not achieve clinical benefit from immunotherapy because of systemic tumor-induced immunosuppression. Monocytic myeloid-derived suppressor cells (M-MDSCs) are implicated as key players in inhibiting anti-tumor immune responses and their frequencies are closely associated with tumor progression. Tumor-derived signals, including signaling via STAT3-COX-2, induce the transformation of monocytic precursors into suppressive M-MDSCs. In a retrospective assessment, we observed that survival of melanoma patients undergoing dendritic cell vaccination was negatively associated with blood M-MDSC levels. Previously, it was shown that platinum-based chemotherapeutics inhibit STAT signaling. Here, we show that cisplatin and oxaliplatin treatment interfere with the development of M-MDSCs, potentially synergizing with cancer immunotherapy. In vitro , subclinical doses of platinum-based drugs prevented the generation of COX-2 + M-MDSCs induced by tumor cells from melanoma patients. This was confirmed in HNSCC patients where intravenous cisplatin treatment drastically lowered M-MDSC frequency while monocyte levels remained stable. In treated patients, expression of COX-2 and arginase-1 in M-MDSCs was significantly decreased after two rounds of cisplatin, indicating inhibition of STAT3 signaling. In line, the capacity of M-MDSCs to inhibit activated T cell responses ex vivo was significantly decreased after patients received cisplatin. These results show that platinum-based chemotherapeutics inhibit the expansion and suppressive activity of M-MDSCs in vitro and in cancer patients. Therefore, platinum-based drugs have the potential to enhance response rates of immunotherapy by overcoming M-MDSC-mediated immunosuppression.

NK cells and solid tumors: therapeutic potential and persisting obstacles

“…Similar benefits have been documented with pharmacological inhibitors of ARG1 in preclinical models of CRC treated with adoptively transferred NK cells [ 201 ]. Additional strategies that efficiently inhibit MDSCs resulting in derepressed NK cell activity include specific chemotherapeutic agents (especially, doxorubicin, gemcitabine and low-dose cyclophosphamide) [ 202 – 206 ], approaches to prevent PGE 2 secretion by MDSCs [ 134 ], as well as all- trans retinoic acid (ATRA), which is known to promote MDSC differentiation and hence limit their immunosuppressive activity [ 207 ]. Interestingly, ATRA can also promote the expression of NK cell-activating ligands including MHC class I polypeptide-related sequence A (MICA) and MICB on malignant cell, de facto rendering them more susceptible to NK cells [ 208 ].…”

Therapeutic strategies for gastric cancer targeting immune cells: Future directions

“…The reduction of circulating and tumor-infiltrating MDSCs can be achieved with some chemotherapy drugs, targeted drugs, all-trans retinoic acid (ATRA), or by blocking the chemokine receptor on MDSCs. Low-dose chemotherapy drugs such as 5-fluorouracil ( 253 ), paclitaxel ( 254 ), gemcitabine ( 255 ), platinum ( 256 ), and Adriamycin ( 257 ) all have been shown to reduce MDSCs in cancer patients. 5-Fluorouracil combined with oxaliplatin reduced the number of MDSCs in the mouse model of GC ( 258 ).…”

“…The targeted drug tyrosine kinase inhibitor sunitinib can modulate anti-tumor immunity by reversing the immunosuppression mediated by MDSCs ( 288 ). In addition to mediating MDSCs migration, the CCR1 and CCR5 silenced in vivo can also lead to repolarization of MDSCs into tumor-killing neutrophils thus playing an anti-tumor effect ( 256 ).…”

Combinatorial regimens of chemotherapeutic agents: A new perspective on raising the heat of the tumor immune microenvironment

“…The same phenomenon can be observed with cytotoxic agents against MDSCs since many chemotherapeutic agents can selectively inhibit MDSC differentiation. Cisplatin has been shown to inhibit the conversion of monocyte precursors to inhibitory M-MDSCs through the regulation of the STAT3-COX-2 signaling axis, overcoming M-MDSC-mediated immunosuppression and improving the overall response rate to cancer immunotherapy ( Van Wigcheren et al, 2021 ). Oxaliplatin is also known to selectively deplete MDSCs, especially Mo-MDSCs, by decreasing the expression of the immunosuppressive functional mediators argininase 1 (ARG1) and NADPH oxidase 2 (NOX2) ( Kim and Kim, 2019 ).…”