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Cancer Res. 2012 Sep 15;72(18):4642-51. doi: 10.1158/0008-5472.CAN-11-3775. Epub 2012 Aug 3.

NFAT1 supports tumor-induced anergy of CD4(+) T cells.

Author information

1
Department of Pathology, Albert Einstein College of Medicine, Bronx, New York 10461, USA.

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.

PMID:
22865456
PMCID:
PMC3445721
DOI:
10.1158/0008-5472.CAN-11-3775
[Indexed for MEDLINE]
Free PMC Article

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