CD4+CD25+ Tregs control the TRAIL-dependent cytotoxicity of tumor-infiltrating DCs in rodent models of colon cancer.
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.
Roux
Stephan
S
INSERM U805, Villejuif, France.
Apetoh
Lionel
L
Chalmin
Fanny
F
Ladoire
Sylvain
S
Mignot
Grégoire
G
Puig
Pierre-Emmanuel
PE
Lauvau
Gregoire
G
Zitvogel
Laurence
L
Martin
François
F
Chauffert
Bruno
B
Yagita
Hideo
H
Solary
Eric
E
Ghiringhelli
François
F
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*
D053221:TNF-Related Apoptosis-Inducing Ligand