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

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-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.

The inhibition of the T-cell immunoglobulin and mucin domain 3 (Tim3) pathway enhances the efficacy of tumor vaccine

“…In a Tim3 transgenic mouse model and a galectin-9 (Tim3 ligand) transgenic mouse model, an increase in MDSCs and inhibition of immune responses are observed [27]. Interestingly, we found that Tim3-hIg expressing therapeutic tumor vaccine did not exhibit an additive inhibitory effect on tumor growth when given in combination with 5-FU, which has recently been reported to selectively kill MDSCs and thus enhance antitumor immunity [33]. Second, Tim3 pathway inhibition may enhance anti-tumor immunity by antagonizing phagocytosis of apoptotic cells and thereby circumventing the immunosuppressive effect of apoptosis.…”

Immune-based mechanisms of cytotoxic chemotherapy: implications for the design of novel and rationale-based combined treatments against cancer

“…48 5-FU was also reported to increase IFN-g production by tumor-specific CD8 T-cells infiltrating the tumor, and to boost T-cell-dependent antitumor responses by in vivo elimination of MDSCs. 49 In both mouse models and patients with esophageal squamous cell carcinoma, neoadjuvant chemotherapy with 5-FU and cisplatin increased the intratumoral trafficking of CD4 and CD8 T-cells. 50,51 In experimental carcinogen-induced adenocarcinomas and fibrosarcomas, doxorubicin treatment enhanced tumor-specific proliferation of CD8 T-cells in tumor-draining lymph nodes (LNs) and promoted tumor infiltration of activated, IFN-g-producing CD8 T-cells.…”

“…68,69 Different strategies to achieve therapeutic depletion of suppressive cell subsets have been described so far. [70][71][72] Gemcitabine kills MDSCs, both in vitro and in vivo, 49,73 with no significant reduction in other cell subsets. The selective loss of MDSCs was accompanied by an increase in the antitumor activity of CD8 T and NK cells.…”

“…88 Docetaxel, another antimicrotubule agent, was shown to polarize MDSCs toward an M1-like phenotype, and to selectively kill MDSCs while sparing the M1-like cells. 89 Recently, 5-FU has been shown to selectively induce MDSC apoptosis in vitro and in vivo, 49,90 resulting in enhanced IFN-g secretion by tumor-infiltrating CD8 T-cells and T-cell-mediated antitumor responses in vivo. 90 Suppressor cells adopt various means to inhibit the antitumor activity of effector lymphocytes.…”

Immune-mediated mechanisms influencing the efficacy of anticancer therapies

“…In subcutaneous and orthotopic cell line transplantation models, gemcitabine, 5-FU and doxorubicin directly induce splenic CD11b + Gr1 + MDSC apoptosis [53][54][55][56]. This chemotherapy-induced MDSC death increases the activity of cytotoxic T cells and contributes to tumor control.…”