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 focused our studies on several transcription factors specifically involved in the regulation of T cell exhaustion in cancer. Among them, NFAT5, an NFAT family member lacking an AP-1 docking site, is highly expressed in exhausted T cells from murine and human tumors and is a central player in tumor-induced exhaustion. While NFAT5 overexpression in T cells led to increased tumor growth, NFAT5 deletion improved tumor control by promoting the accumulation of more functional tumor-specific CD8+ T cells. Conversely, NFAT5 had no effect on chronic infection-induced T cell exhaustion. Taking advantage of our NFAT5-activity reporter mice, we found tumor specific mechanisms regulating the specific role of NFAT5 in tumors. In a more translational approach, we developed NFAT5 specific inhibitors. We demonstrated that they blocked NFAT5 activity in T cells both in vitro and in vivo, without affecting organs such as the kidney or the heart, where NFAT5 activity has central roles. This blocking led to a decrease in T cell exhaustion, showing the potential of such an approach for increasing anti-tumor response.

Grégory Verdeil is invited by Laurie Choux.