NFAT1 Supports Tumor-induced Anergy of CD4+ T Cells

• Published in: Cancer research (Chicago, Ill.) Vol. 72; no. 18; pp. 4642 - 4651
• Main Authors: ABE, Brian T, SHIN, Daniel S, MOCHOLI, Enric, MACIAN, Fernando
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15.09.2012
• Subjects: Adoptive Transfer; Animals; Antineoplastic agents; Biological and medical sciences; CD4-Positive T-Lymphocytes - immunology; Clonal Anergy - immunology; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Medical sciences; Melanoma - immunology; Melanoma - metabolism; Mice; Mice, Transgenic; NFATC Transcription Factors - immunology; NFATC Transcription Factors - metabolism; Pharmacology. Drug treatments; Real-Time Polymerase Chain Reaction; Tumor Escape - immunology; Tumor Microenvironment - physiology; Tumors; Transcription factor NFAT; CD4 T lymphocyte; Malignant tumor; Anergy; Cancer
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-11-3775

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.