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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.
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Contributor : Grégoire Mignot Connect in order to contact the contributor
Submitted on : Friday, January 29, 2010 - 5:28:15 PM
Last modification on : Saturday, June 25, 2022 - 9:08:19 PM
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Stephan Roux, Lionel Apetoh, Fanny Chalmin, Sylvain Ladoire, Grégoire Mignot, et al.. CD4+CD25+ Tregs control the TRAIL-dependent cytotoxicity of tumor-infiltrating DCs in rodent models of colon cancer.. Journal of Clinical Investigation, American Society for Clinical Investigation, 2008, 118 (11), pp.3751-61. ⟨10.1172/JCI35890⟩. ⟨inserm-00451698⟩



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