5-Fluorouracil Selectively Kills Tumor-Associated Myeloid-Derived Suppressor Cells Resulting in Enhanced T Cell–Dependent Antitumor Immunity

Cancer Research - Tập 70 Số 8 - Trang 3052-3061 - 2010
Julie Vincent1, Grégoire Mignot1, Fanny Chalmin1, Sylvain Ladoire1, Mélanie Bruchard1, Angélique Chevriaux1, François Martin1, Lionel Apétoh1, Cédric Rébé1, François Ghiringhelli1
1Authors' Affiliations: 1INSERM Research Center 866, AVENIR Team; 2Faculty of Medicine, University of Burgundy, 3Anti-Cancer Center, Georges François Leclerc, Dijon, France; and 4Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts

Tóm tắt

AbstractMyeloid-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-γ 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. Cancer Res; 70(8); 3052–61. ©2010 AACR.

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Cancer Research

Tập 70 Số 8

3052-3061

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