Fiche publication
Date publication
novembre 2008
Journal
The Journal of clinical investigation
Auteurs
Membres identifiés du Cancéropôle Est :
Pr GHIRINGHELLI François
,
Dr LADOIRE Sylvain
,
Dr CHALMIN Fanny
Tous les auteurs :
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
Lien Pubmed
Résumé
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.
Mots clés
Animals, CD4-Positive T-Lymphocytes, immunology, Cell Line, Tumor, Cells, Cultured, Colonic Neoplasms, immunology, Dendritic Cells, cytology, Disease Models, Animal, Male, Mice, Mice, Inbred BALB C, Mice, Nude, Neoplasms, immunology, Rats, Rats, Inbred Strains, T-Lymphocytes, Regulatory, immunology, TNF-Related Apoptosis-Inducing Ligand, immunology
Référence
J. Clin. Invest.. 2008 Nov;118(11):3751-61
