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

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


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adoptive Transfer
  • Animals
  • CD4-Positive T-Lymphocytes / immunology*
  • Clonal Anergy / immunology*
  • Disease Models, Animal
  • Enzyme-Linked Immunosorbent Assay
  • Melanoma / immunology*
  • Melanoma / metabolism*
  • Mice
  • Mice, Transgenic
  • NFATC Transcription Factors / immunology*
  • NFATC Transcription Factors / metabolism
  • Real-Time Polymerase Chain Reaction
  • Tumor Escape / immunology*
  • Tumor Microenvironment / physiology


  • NFATC Transcription Factors