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

Autor:	Van Wigcheren GF; Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboudumc, Nijmegen, The Netherlands.; Oncode Institute, Utrecht, The Netherlands., De Haas N; Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboudumc, Nijmegen, The Netherlands., Mulder TA; Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboudumc, Nijmegen, The Netherlands.; Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden., Horrevorts SK; Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboudumc, Nijmegen, The Netherlands., Bloemendal M; Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboudumc, Nijmegen, The Netherlands.; Department of Medical Oncology, Radboudumc, Nijmegen, The Netherlands., Hins-Debree S; Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboudumc, Nijmegen, The Netherlands., Mao Y; Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.; Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden., Kiessling R; Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden., van Herpen CML; Department of Medical Oncology, Radboudumc, Nijmegen, The Netherlands., Flórez-Grau G; Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboudumc, Nijmegen, The Netherlands., Hato SV; Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboudumc, Nijmegen, The Netherlands., De Vries IJM; Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboudumc, Nijmegen, The Netherlands.
Jazyk:	angličtina
Zdroj:	Oncoimmunology [Oncoimmunology] 2021 Jun 27; Vol. 10 (1), pp. 1935557. Date of Electronic Publication: 2021 Jun 27 (Print Publication: 2021).
DOI:	10.1080/2162402X.2021.1935557
Abstrakt:	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. Competing Interests: The authors declare that they have no conflict of interest. (© 2021 The Author(s). Published with license by Taylor & Francis Group, LLC.)
Databáze:	MEDLINE
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