NFAT5 induction by the tumor microenvironment enforces CD8 T cell exhaustion [ATAC]
Persistent exposure to antigen during chronic infection or cancer renders T cells dysfunctional. The molecular mechanisms regulating this state of exhaustion are thought to be common in infection and cancer, despite obvious differences in their microenvironments. We discovered that NFAT5, an NFAT family member lacking an AP-1 docking site, is highly expressed in exhausted T cells responding to chronic infection and tumors but is a central player selectively in tumor-induced exhaustion. While NFAT5 overexpression in CD8+ T cells reduced tumor control, NFAT5 deletion improved tumor control by promoting the accumulation of tumor-specific CD8 T cells that expressed less TOX and PD-1 and produced more cytokines specifically among precursor exhausted cells. Conversely, NFAT5 did not promote T cell exhaustion during chronic infection. While NFAT5 expression was induced by TCR triggering, its transcriptional activity was specific to the tumor microenvironment and required hyperosmolarity. NFAT5 thus promotes CD8 T cell exhaustion in a tumor-selective fashion. Overall design: 48 hours activated NFAT5flox/flox CD4-Cre-/- (WT) or NFAT5flox/flox CD4-Cre+/- (NFAT5 KO) P14 CD8 T cells were transferred into mice bearing subcutaneous gp33-expressing B16 melanoma (B16-gp33). Seven days post transfer CD8 TILs were sorted from the tumors and processed for scATAC sequencing.