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

Oncoimmunology. 2021 Jun 27;10(1):1935557. doi: 10.1080/2162402X.2021.1935557. eCollection 2021.

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.

Keywords: Cancer; MDSC; cisplatin; immunotherapy; platinum-based chemotherapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cisplatin / pharmacology
  • Humans
  • Melanoma* / drug therapy
  • Monocytes
  • Myeloid-Derived Suppressor Cells*
  • Retrospective Studies

Substances

  • Cisplatin

Grants and funding

N.H. and S.V.H. are supported by a grant from the Dutch Cancer Society and Alpe deHuZes foundation (KUN2013-5958). This work is also supported by KWO grant 10673 from the Dutch Cancer Society and Health Holland, Top Sector Life Sciences & Health grant LSHM18056-SGF. T.A.M., Y.M. and R.K. are supported by grants from The Swedish Research Council, The European Research Council (FP7 Marie Curie re-integration grant), Karolinska Institutet, Jeanssons Stiftelser, Åke Wibergs Stiftelse, Magnus Bergvalls Stiftelse, Fredrik och Ingrid Thurings Stiftelse, Stiftelsen Clas Groschinskys Minnesfond. Y.M. is supported by a starting grant from the Science for Life Laboratory and grants from the Swedish Childhood Cancer Foundation (TJ2019-0057). R.K. is supported by grants from The Swedish Cancer Society 190104Pj01H, the Cancer Society in Stockholm 194123, the Swedish Medical Research Council 2019-01212 and Stockholm City Council Project Grant LS 2018-1157. I.J.M.V. is recipient of Vici grant 918.14.655 from The Netherlands Organisation for Scientific Research.