title: NFAT1 supports tumor-induced anergy of CD4(+) T cells.
abstract: Cancer cells express antigens that elicit T cell-mediated responses, but these responses are limited during malignant progression by the development of immunosuppressive mechanisms in the tumor microenvironment that drive immune escape. T-cell hyporesponsiveness can be caused by clonal anergy or adaptive tolerance, but the pathophysiological roles of these processes in specific tumor contexts has yet to be understood. In CD4+ T cells, clonal anergy occurs when the T-cell receptor is activated in the absence of a costimulatory signal. Here we report that the key T-cell transcription factor NFAT mediates expression of anergy-associated genes in the context of cancer. Specifically, in a murine model of melanoma, we found that cancer cells induced anergy in antigen-specific CD4+ T-cell populations, resulting in defective production of several key effector cytokines. NFAT1 deficiency blunted the induction of anergy in tumor antigen-specific CD4+ T cells, enhancing antitumor responses. These investigations identified tumor-induced T-cell hyporesponsiveness as a form of clonal anergy, and they supported an important role for CD4+ T-cell anergy in driving immune escape. By illustrating the dependence of tumor-induced CD4+ T-cell anergy on NFAT1, our findings open the possibility of targeting this transcription factor to improve the efficacy of cancer immunotherapy or immunochemotherapy.
authors.affiliation: Department of Pathology, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
authors.forename: Brian T
authors.initials: BT
authors.lastname: Abe
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Shin
authors.forename: Enric
authors.initials: E
authors.lastname: Mocholi
authors.forename: Fernando
authors.initials: F
authors.lastname: Macian
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D017635:Clonal Anergy / Q000276:immunology*; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D008545:Melanoma / Q000276:immunology* / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D050778:NFATC Transcription Factors / Q000276:immunology* / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D019139:Tumor Escape / Q000276:immunology*; D059016:Tumor Microenvironment / Q000502:physiology
chemical_list: D050778:NFATC Transcription Factors