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Tumors induce regulatory dendritic cells that suppress CD8+ T cell antitumor immunity
Author(s) -
Norian Lyse A.,
Rodriguez Paulo,
O’Mara Leigh. A.,
Zabaleta Jovanny,
Ochoa Augusto,
Cella Marina,
Allen Paul M.
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.1078.4
Subject(s) - t cell , cytotoxic t cell , cd8 , immune system , biology , dendritic cell , arginase , microbiology and biotechnology , acquired immune system , cancer research , cd11c , regulatory t cell , immunology , il 2 receptor , arginine , in vitro , phenotype , biochemistry , amino acid , gene
Dendritic cells have a critical impact on the outcome of adaptive immune responses against growing tumors. Using a murine model of spontaneously arising mammary carcinoma, we found that phenotypically mature, MHC Cl II + /CD11b + /CD11c high tumor infiltrating dendritic cells (TIDCs) act as regulatory DCs to suppress CD8 + T cell function, resulting in diminished T cell‐based antitumor immunity in vivo. Stimulation of naive T cells with TIDCs resulted in an altered cell fate program characterized by cell cycle arrest, impaired IFNg production, and anergy. Suppression by TIDCs overcame stimulatory signals provided by standard DCs and occurred independently of cognate interactions with T cells. TIDC suppression was mediated by arginase metabolism of the amino acid L‐arginine; blockade of arginase, but not iNOS, restored T cell proliferation. Thus, the tumor microenvironment can induce phenotypically mature MHC Cl II + TIDCs to acquire regulatory functions and utilize arginine metabolism to suppress protective CD8 + T cell based antitumor immunity. Our results suggest that targeting these cells in vivo may enhance the efficacy of T cell based antitumor immunotherapies.