5-Fluorouracil selectively kills tumor-associated myeloid-derived suppressor cells resulting in enhanced T cell-dependent antitumor immunity

• Published in: Cancer research (Chicago, Ill.) Ill.), 2010-04, Vol.70 (8), p.3052-3061
• Main Authors: Vincent, Julie, Mignot, Grégoire, Chalmin, Fanny, Ladoire, Sylvain, Bruchard, Mélanie, Chevriaux, Angélique, Martin, François, Apetoh, Lionel, Rébé, Cédric, Ghiringhelli, François
• Format: Article
• Language: English
• Subjects: Animals; Antimetabolites, Antineoplastic - pharmacology; Apoptosis; CD8-Positive T-Lymphocytes - cytology; Cell Line, Tumor; Dendritic Cells - drug effects; Deoxycytidine - analogs & derivatives; Deoxycytidine - pharmacology; Flow Cytometry; Fluorouracil - pharmacology; Immune System; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Nude; Neoplasm Transplantation; T-Lymphocytes - immunology; T-Lymphocytes - metabolism
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-09-3690

Myeloid-derived suppressor cells (MDSC) accumulate in the spleen and tumor bed during tumor growth. They contribute to the immune tolerance of cancer notably by inhibiting the function of CD8(+) T cells. Thus, their elimination may hamper tumor growth by enhancing antitumor T-cell functions. We have previously reported that some anticancer agents relied on T cell-dependent anticancer responses to achieve maximal efficacy. However, the effect of anticancer agents on MDSC has remained largely unexplored. In this study, we observed that gemcitabine and 5-fluorouracil (5FU) were selectively cytotoxic on MDSC. In vivo, the treatment of tumor-bearing mice with 5FU led to a major decrease in the number of MDSC in the spleens and tumor beds of animals whereas no significant effect on T cells, natural killer cells, dendritic cells, or B cells was noted. Interestingly, 5FU showed a stronger efficacy over gemcitabine to deplete MDSC and selectively induced MDSC apoptotic cell death in vitro and in vivo. The elimination of MDSC by 5FU increased IFN-gamma production by tumor-specific CD8(+) T cells infiltrating the tumor and promoted T cell-dependent antitumor responses in vivo. Altogether, these findings suggest that the antitumor effect of 5FU is mediated, at least in part, by its selective cytotoxic action on MDSC.