Abstract
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.
Highlights
Myeloid-derived suppressor cells (MDSC) accumulate in the spleen and tumor bed during tumor growth
To investigate whether conventional anticancer agents were able to affect the biology of MDSC, we designed an in vivo drug screening assay in which we tested the effect of anticancer agents on the proportion of MDSC within tumor-bearing mice
Our results show for the first time that 5FU was able to reduce the number of MDSC in tumor beds by triggering their apoptotic cell death
Summary
Myeloid-derived suppressor cells (MDSC) accumulate in the spleen and tumor bed during tumor growth. Myeloid-derived suppressor cells (MDSC) have been identified as a population of immature myeloid cells with the ability to suppress T-cell activation in humans and mice [1,2,3] These cells accumulate in the blood, lymph nodes, bone marrow, and at tumor sites in many human cancers and animal tumor models, and inhibit both adaptive and innate immunity [4]. We and others have previously reported that some anticancer agents, in addition to their direct cytotoxic effects on tumor cells, feature the ability to promote the activation of the immune system of the host, resulting in enhanced antitumor responses [16, 17]. We observed that 5FUmediated MDSC depletion triggered an increase in IFN-γ production by tumor-specific CD8+ T cells infiltrating the tumor bed and promoted a T-dependent antitumor effect These results suggest that, beyond its direct cytotoxic effect. On tumor cells, 5FU possesses immunogenic properties that rely on the in vivo elimination of MDSC
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