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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Authors | 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 |
Journal | The Journal of clinical investigation
(J Clin Invest)
Vol. 118
Issue 11
Pg. 3751-61
(Nov 2008)
ISSN: 0021-9738 [Print] United States |
PMID | 18830416
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- TNF-Related Apoptosis-Inducing Ligand
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Topics |
- Animals
- CD4-Positive T-Lymphocytes
(immunology, metabolism)
- Cell Line, Tumor
- Cells, Cultured
- Colonic Neoplasms
(immunology, metabolism)
- Dendritic Cells
(cytology, immunology, metabolism)
- Disease Models, Animal
- Male
- Mice
- Mice, Inbred BALB C
- Mice, Nude
- Neoplasms
(immunology, metabolism)
- Rats
- Rats, Inbred Strains
- T-Lymphocytes, Regulatory
(immunology, metabolism)
- TNF-Related Apoptosis-Inducing Ligand
(immunology, metabolism, toxicity)
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