1. CD4+CD25+ Tregs control the TRAIL-dependent cytotoxicity of tumor-infiltrating DCs in rodent models of colon cancer
- Author
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Bruno Chauffert, Grégoire Lauvau, Eric Solary, Hideo Yagita, Laurence Zitvogel, François Martin, Stephan Roux, Fanny Chalmin, Pierre Emmanuel Puig, Grégoire Mignot, Sylvain Ladoire, François Ghiringhelli, Lionel Apetoh, Role des Cellules Dendritiques Dans la Regulation des Effecteurs de l'Immunite Antitumorale, Université Paris-Sud - Paris 11 ( UP11 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Lipides - Nutrition - Cancer (U866) ( LNC ), Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ), Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc ( CRLCC - CGFL ), Immunologie des Maladies Infectieuses Allergiques et Autoimmunes, Université Nice Sophia Antipolis ( UNS ), Université Côte d'Azur ( UCA ) -Université Côte d'Azur ( UCA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Department of Immunology, Juntendo University School of Medicine, We received grant support from Fondation pour la Recherche Médicale (to S. Roux and L. Apetoh), Association pour la Recherche contre le Cancer (to G. Mignot), and Institut National de la Santé et de la Recherche Médicale (to F. Ghiringhelli). This work was supported by special grants from the Ligue contre le Cancer de Bourgogne and the Association pour la Recherche contre le Cancer., Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM), Lipides - Nutrition - Cancer (U866) (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Mignot, Grégoire, and Université Nice Sophia Antipolis (1965 - 2019) (UNS)
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CD4-Positive T-Lymphocytes ,Male ,MESH : Rats, Inbred Strains ,T-Lymphocytes, Regulatory ,MESH : TNF-Related Apoptosis-Inducing Ligand ,TNF-Related Apoptosis-Inducing Ligand ,MESH : T-Lymphocytes, Regulatory ,Mice ,0302 clinical medicine ,Neoplasms ,Cytotoxic T cell ,[ SDV.IMM ] Life Sciences [q-bio]/Immunology ,MESH: Animals ,MESH: Neoplasms ,IL-2 receptor ,Cytotoxicity ,Cells, Cultured ,0303 health sciences ,Mice, Inbred BALB C ,MESH: Dendritic Cells ,MESH : Rats ,MESH: CD4-Positive T-Lymphocytes ,MESH : Mice, Nude ,hemic and immune systems ,General Medicine ,MESH: Rats, Inbred Strains ,3. Good health ,MESH : Colonic Neoplasms ,MESH : CD4-Positive T-Lymphocytes ,Colonic Neoplasms ,[SDV.IMM]Life Sciences [q-bio]/Immunology ,MESH: TNF-Related Apoptosis-Inducing Ligand ,MESH: Cells, Cultured ,Research Article ,MESH: Cell Line, Tumor ,[SDV.IMM] Life Sciences [q-bio]/Immunology ,MESH: Rats ,MESH : Male ,MESH: Mice, Inbred BALB C ,Mice, Nude ,chemical and pharmacologic phenomena ,Biology ,03 medical and health sciences ,Immune system ,Cell Line, Tumor ,MESH : Cells, Cultured ,MESH : Mice ,MESH: Mice, Nude ,Animals ,MESH: Mice ,MESH : Mice, Inbred BALB C ,030304 developmental biology ,MESH: Colonic Neoplasms ,Innate immune system ,MESH : Cell Line, Tumor ,MESH: T-Lymphocytes, Regulatory ,TLR9 ,Rats, Inbred Strains ,Dendritic Cells ,MESH : Neoplasms ,MESH : Disease Models, Animal ,MESH: Male ,Rats ,TLR2 ,Disease Models, Animal ,MESH : Dendritic Cells ,Immunology ,TLR4 ,MESH : Animals ,MESH: Disease Models, Animal ,030215 immunology - Abstract
International audience; 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.
- Published
- 2008
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