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Transfer of Manipulated Tumor-associated Neutrophils into Tumor-Bearing Mice to Study their Angiogenic Potential In Vivo
Published on: July 20, 2019
NFAT1 supports tumor-induced anergy of CD4(+) T cells
Brian T Abe1, Daniel S Shin, Enric Mocholi
1Department 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.
Insights
Cancer cells can evade immune responses by inducing T-cell anergy, a state of hyporesponsiveness. Targeting the transcription factor NFAT1 can potentially enhance cancer immunotherapies by restoring T-cell function.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- Malignant progression involves immunosuppressive mechanisms within the tumor microenvironment, leading to immune escape.
- T-cell hyporesponsiveness, including clonal anergy and adaptive tolerance, contributes to immune escape but its role in specific cancers is unclear.
- Clonal anergy in CD4+ T cells arises from T-cell receptor activation without costimulation.
Purpose of the Study:
- To investigate the role of the transcription factor NFAT in mediating T-cell anergy in cancer.
- To determine if tumor-induced T-cell hyporesponsiveness is a form of clonal anergy.
- To explore the potential of targeting NFAT for cancer immunotherapy.
Main Methods:
- Utilized a murine melanoma model to study antigen-specific CD4+ T cells.
- Assessed the expression of anergy-associated genes mediated by NFAT.
- Investigated the impact of NFAT1 deficiency on T-cell responses and antitumor immunity.
Main Results:
- Cancer cells induced clonal anergy in antigen-specific CD4+ T cells, impairing effector cytokine production.
- NFAT1 deficiency reversed anergy induction in tumor-specific CD4+ T cells, boosting antitumor responses.
- Confirmed tumor-induced T-cell hyporesponsiveness as a form of clonal anergy.
Conclusions:
- CD4+ T-cell anergy plays a significant role in cancer immune escape.
- NFAT1 is crucial for tumor-induced CD4+ T-cell anergy.
- Targeting NFAT1 presents a potential strategy to enhance cancer immunotherapy efficacy.
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