CD4+CD25+ Tregs control the TRAIL-dependent cytotoxicity of tumor-infiltrating DCs in rodent models of colon cancer
Stephan Roux, Lionel Apetoh, Fanny Chalmin, Sylvain Ladoire, Grégoire Mignot, Pierre-Emmanuel Puig, Gregoire Lauvau, Laurence Zitvogel, François Martin, Bruno Chauffert, Hideo Yagita, Eric Solary, François Ghiringhelli
Stephan Roux, Lionel Apetoh, Fanny Chalmin, Sylvain Ladoire, Grégoire Mignot, Pierre-Emmanuel Puig, Gregoire Lauvau, Laurence Zitvogel, François Martin, Bruno Chauffert, Hideo Yagita, Eric Solary, François Ghiringhelli
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Research Article

CD4+CD25+ Tregs control the TRAIL-dependent cytotoxicity of tumor-infiltrating DCs in rodent models of colon cancer

Abstract

Tumors that progress do so via their ability to escape the antitumor immune response through several mechanisms, including developing ways to induce the differentiation and/or recruitment of CD4+CD25+ Tregs. The Tregs, in turn, inhibit the cytotoxic function of T cells and NK cells, but whether they have an effect on the cytotoxic function of tumor-infiltrating DCs (TIDCs) has not been determined. Here we have shown, in 2 rodent models of colon cancer, that CD4+CD25+ Tregs inhibit the ability of CD11b+ TIDCs to mediate TNF-related apoptosis-inducing ligand–induced (TRAIL-induced) tumor cell death. In both models of cancer, combination treatment with Mycobacterium bovis Bacillus Calmette-Guérin (BCG), which activates the innate immune system via TLR2, TLR4, and TLR9, and cyclophosphamide (CTX), which depletes Tregs, eradicated the tumors. Further analysis revealed that the treatment led to a marked increase in the number of CD11b+ TIDCs that killed the tumor cells via a TRAIL-dependent mechanism. Furthermore, acquisition of TRAIL expression by the CD11b+ TIDCs was induced by BCG and dependent on signaling through TLR2, TLR4, and TLR9. In vivo transfer of Tregs abrogated the ability of BCG to induce CD11b+ TIDCs to express TRAIL and thereby nullified the efficacy of the CTX-BCG treatment. Our data have therefore delineated what we believe to be a novel mechanism by which Tregs inhibit the antitumor immune response.

Authors

Stephan Roux, Lionel Apetoh, Fanny Chalmin, Sylvain Ladoire, Grégoire Mignot, Pierre-Emmanuel Puig, Gregoire Lauvau, Laurence Zitvogel, François Martin, Bruno Chauffert, Hideo Yagita, Eric Solary, François Ghiringhelli

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Figure 7

Treg control TRAIL-mediated antitumor effect of CTX-BCG treatment in vivo.

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Treg control TRAIL-mediated antitumor effect of CTX-BCG treatment in viv...
(A) Unstimulated or overnight BCG stimulated BM-DCs (1–2 × 106 cells) were injected intratumorally in nude mice 2, 4, 6, and 10 days after subcutaneous CT26 cell injection (n = 5 in each group). (B) FACS analysis of TRAIL expression in CD11b+ TIDCs (CD45+) from CT26 untreated or treated tumors. The day of the first BCG injection, 1 × 106 Tregs, 1 × 106 Tconvs, or 100 μl PBS were injected intravenously, and mice were killed 2 days after the second BCG intratumoral injection. Numbers indicate the percentage of cells ± SD. (C) Four groups of 5 BALB/c mice received a subcutaneous injection of 5 × 105 CT26 tumor cells. Seven days later, mice received the combined treatment alone or in combination with intratumoral or i.p. injection of Z-VAD-fmk or anti-TRAIL mAb respectively. Untreated mice represent control group. For each experiment, animals were monitored twice a week for tumor volume. Values in A and C represent mean ± SEM. *P < 0.05.