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

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)3751-3761
Number of pages11
JournalJournal of Clinical Investigation
Volume118
Issue number11
DOIs
StatePublished - Nov 3 2008
Externally publishedYes

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Colonic Neoplasms
Rodentia
Neoplasms
Bacillus
TNF-Related Apoptosis-Inducing Ligand
Mycobacterium bovis
Natural Killer Cells
Cyclophosphamide
Immune System
Cell Death
T-Lymphocytes

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Roux, S., Apetoh, L., Chalmin, F., Ladoire, S., Mignot, G., Puig, P. E., ... Ghiringhelli, F. (2008). CD4+CD25+ Tregs control the TRAIL-dependent cytotoxicity of tumor-infiltrating DCs in rodent models of colon cancer. Journal of Clinical Investigation, 118(11), 3751-3761. https://doi.org/10.1172/JCI35890

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

In: Journal of Clinical Investigation, Vol. 118, No. 11, 03.11.2008, p. 3751-3761.

Research output: Contribution to journalArticle

Roux, S, Apetoh, L, Chalmin, F, Ladoire, S, Mignot, G, Puig, PE, Lauvau, G, Zitvogel, L, Martin, F, Chauffert, B, Yagita, H, Solary, E & Ghiringhelli, F 2008, 'CD4+CD25+ Tregs control the TRAIL-dependent cytotoxicity of tumor-infiltrating DCs in rodent models of colon cancer', Journal of Clinical Investigation, vol. 118, no. 11, pp. 3751-3761. https://doi.org/10.1172/JCI35890
Roux, Stephan ; Apetoh, Lionel ; Chalmin, Fanny ; Ladoire, Sylvain ; Mignot, Grégoire ; Puig, Pierre Emmanuel ; Lauvau, Gregoire ; Zitvogel, Laurence ; Martin, François ; Chauffert, Bruno ; Yagita, Hideo ; Solary, Eric ; Ghiringhelli, François. / CD4+CD25+ Tregs control the TRAIL-dependent cytotoxicity of tumor-infiltrating DCs in rodent models of colon cancer. In: Journal of Clinical Investigation. 2008 ; Vol. 118, No. 11. pp. 3751-3761.
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AU - Ladoire, Sylvain

AU - Mignot, Grégoire

AU - Puig, Pierre Emmanuel

AU - Lauvau, Gregoire

AU - Zitvogel, Laurence

AU - Martin, François

AU - Chauffert, Bruno

AU - Yagita, Hideo

AU - Solary, Eric

AU - Ghiringhelli, François

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