Restoration of Antitumor Immunity Through Selective Inhibition of Myeloid Derived Suppressor Cells by Anticancer Therapies

L.      Apetoh; F.      Vegran; S.      Ladoire; F.      Ghiringhelli

Abstract

Accumulating evidence suggests that the success of some anticancer therapies not only relies on their direct cytotoxicity on tumor cells but also on their ability to promote anticancer immune responses. However, immunosuppressive cells such as Myeloid Derived Suppressor Cells (MDSC) that are generated during tumor progression blunt antitumor immune responses and thus represent a major obstacle to the clinical implementation of immunotherapy protocols. We have recently identified 5-Fluorouracil (5-FU) as an anticancer agent that selectively induced MDSC apoptotic cell death in vitro and in vivo. The elimination of MDSC by 5-FU increased IFNγ secretion by tumor specific CD8+ T cells infiltrating the tumor and promoted Tcell dependent antitumor responses in vivo, suggesting that some anticancer therapies can reverse tumormediated immunosuppression. Here, we review the molecular pathways leading to the induction of MDSC in cancer and discuss how different anticancer agents successfully target these cells in vivo, thereby restoring potent anticancer immunity.

Keywords: Myeloid-derived suppressor cells, T-cells, adaptive immunity, anticancer immunity, immunomodulation, methotrexate, rheumatoid arthritis, cyclosphosphamide, multiple sclerosis, immunosuppression, daunorubicin, doxorubicin, tumoricidal activity, anthracyclines, chemotherapeutic agents