Alternate transcriptional programs activated by NFAT and their relevance to cancer immunotherapy

(a) T cell hyporesponsiveness (anergy/ exhaustion). We have shown that NFAT induces additional transcriptional programs under conditions where it does not cooperate with AP-1 [A, B, 9-11]. In both CD4⁺ and CD8⁺ T cells, NFAT without AP-1 induces a negative feedback program in which upregulation of phosphatases, E3 ligases and inhibitory cell surface receptors results in diminished T cell responses; this negative feedback program represents the transcriptional basis for two clinically important unresponsive states of T cells, CD4⁺ T cell “anergy” and CD8⁺ T cell “exhaustion” [A, B, 9-11; PMID 15999806]. Anergized/exhausted T cells upregulate inhibitory cell surface receptors including PD-1, TIM3, CTLA4, LAG3, TIGIT. Cancer patients have recently been treated with blocking antibodies to inhibitory receptors (“checkpoint blockade” therapy) with remarkable success, revolutionizing cancer immunotherapy. (b) NFAT and FOXP3 in regulatory T cells. In collaboration with Dr. Lin Chen, we solved the crystal structure of a cooperative complex of NFAT with FOXP3, the lineage-defining marker for regulatory T cells; by mutating the NFAT-interacting surface of FOXP3, we showed that the NFAT-FOXP3 interaction is required for the optimal function of FOXP3 [12]. We also showed that FOXP3 forms a “domain-swapped” dimer, and that the dimer interface is necessary for the full transcriptional function of FOXP3 (PMID: 21458306). Together, these studies represent one of the few comprehensive attempts at structure-function analysis of FOXP3.   9. Scott-Browne JP, López-Moyado IF, Trifari S, Wong V, Chavez L, Rao A, Pereira RM. Dynamic Changes in Chromatin Accessibility Occur in CD8+ T Cells Responding to Viral Infection. Immunity 2016; 45: 1327-1340. PMC5214519 10.Mognol G*, Spreafico R*, Wong V*, Scott-Browne JP, Togher S, Hoffmann A, Hogan PG, Trifari S, Rao A. Exhaustion associated regulatory regions in CD8⁺ tumor-infiltrating T cells. Proc Natl Acad Sci USA 2017; 114: E2776-E2785. 11.Chen J, López-Moyado IF, Seo H, Lio C-W J, Hempleman LJ, Sekiya T, Yoshimura A, Scott-Browne JP, Rao A. Nr4a transcription factors limit CAR T cell function in solid tumours. Nature 2019, in press. 12. Wu Y*, Borde M*, Heissmeyer V, Feuerer M, Lapan AD, Stroud JC, Bates DL, Guo L, Han A, Ziegler SF, Mathis D, Benoist C, Chen L, Rao A. FOXP3 controls T regulatory function through cooperation with NFAT. Cell 2006; 126: 375-387.