Tumor recognition and elimination by the immune system is key to limiting cancer development. The T cell arm of the adaptive immune system has the potential for detecting and removing transformed cells expressing neo-antigens, however cancer cells have been shown to evade the immune system by inducing tolerance particularly in the CD4+ T helper cell compartment.
CD4+ T cells are properly activated by signaling through the antigen-specific T cell receptor (TCR) and co-stimulatory receptors. In the absence of co-stimulatory receptor engagement, suboptimally activated T cells enter a state of anergy and become unresponsive to subsequent proper stimulations. The TCR-activated, calcineurin-dependent transcription factor NFAT1 forms homodimers in the nucleus of T cells receiving anergizing stimuli and induces the expression of anergic genes, including Grail and Casp3 that are essential to maintain the T cell in this tolerized state. We therefore hypothesized that tumors induce tolerance in CD4+ T cells through an NFAT1-dependent mechanism, allowing tumor-induced immunosuppression and escape from immune surveillance. We observed tumor-induced CD4+ T cell anergy in tumor-infiltrating T cells and draining lymph nodes of OT-II TCR-transgenic mice challenged with B16-OVA melanoma. These T cells showed defects in IL-2 and IFN-γ production and proliferation, and up-regulated the expression of Grail. Supporting the role of NFAT1-regulated programs of T cell tolerance in the context of tumor immune escape, Nfat1-/- OT-II mice showed increased resistance to tumor growth when challenged with B16-OVA melanoma compared to wildtype controls in a CD4+ T cell specific manner. Additionally, CD4+ T cells from these mice produced IL-2 and IFN-γ, and did not up-regulate anergy associated genes.
Our results also showed that tumor specific cells produced less IL-17A compared to controls suggesting possible tumor-induced Th17 cell anergy. Furthermore, in vitro anergized Th17 cells up-regulated anergic genes and were hypo-responsive upon full stimulation.
As NFAT1 homodimers are involved in the expression of several anergic genes, we synthesized peptides that inhibit NFAT1 homodimers. These inhibitors decreased Grail expression and increased proliferation in re-stimulated T cells previously anergized in vitro. These results pave a new therapeutic avenue targeting NFAT1 homodimers to augment T cell responses in tumor immunity.
|School Location:||United States -- New York|
|Source:||DAI-B 73/07(E), Dissertation Abstracts International|
|Keywords:||CD4+ T cells, Immune tolerance|
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