title: 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.affiliation: INSERM U805, Villejuif, France.
authors.forename: Stephan
authors.initials: S
authors.lastname: Roux
authors.forename: Lionel
authors.initials: L
authors.lastname: Apetoh
authors.forename: Fanny
authors.initials: F
authors.lastname: Chalmin
authors.forename: Sylvain
authors.initials: S
authors.lastname: Ladoire
authors.forename: Grégoire
authors.initials: G
authors.lastname: Mignot
authors.forename: Pierre-Emmanuel
authors.initials: PE
authors.lastname: Puig
authors.forename: Gregoire
authors.initials: G
authors.lastname: Lauvau
authors.forename: Laurence
authors.initials: L
authors.lastname: Zitvogel
authors.forename: François
authors.initials: F
authors.lastname: Martin
authors.forename: Bruno
authors.initials: B
authors.lastname: Chauffert
authors.forename: Hideo
authors.initials: H
authors.lastname: Yagita
authors.forename: Eric
authors.initials: E
authors.lastname: Solary
authors.forename: François
authors.initials: F
authors.lastname: Ghiringhelli
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D003110:Colonic Neoplasms / Q000276:immunology / Q000378:metabolism; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D004195:Disease Models, Animal; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009369:Neoplasms / Q000276:immunology / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000276:immunology / Q000378:metabolism / Q000633:toxicity*
chemical_list: D053221:TNF-Related Apoptosis-Inducing Ligand