Abstract IA02: The T cell ‘exhaustion’ transcriptional program downstream of NFAT

Abstract ‘Exhaustion’ describes a spectrum of states of CD8 tumor-infiltrating lymphocytes (TILs) that have limited capacity to mount an effector response, thereby forming one of the major barriers to immune therapies against solid tumors. We found previously that the transcription factor NFAT drives the effector T cell transcriptional response when it pairs with AP-1 (Fos-Jun) dimers on composite binding sites in gene promoters and enhancers. Later, we found that NFAT initiates exhaustion, when it is activated under conditions that fail to induce sufficient levels of AP-1. The NFAT transcriptional targets NR4A and TOX proteins have key downstream roles in implementing the exhaustion program and in promoting TIL survival in the challenging environment of a solid tumor. However, the specific transcriptional mechanisms that redirect NFAT away from genes of the effector immune response and to genes that initiate exhaustion have not been defined. Here we examine the contributions of specific protein partners of NFAT that we identified by proximity labeling, and shed new light on the early transcriptional mechanisms of T cell exhaustion. Citation Format: Patrick G. Hogan. The T cell ‘exhaustion’ transcriptional program downstream of NFAT [abstract]. In: Proceedings of the AACR Immuno-Oncology Conference (AACR IO): Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2026 Feb 18-21; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2026;14(2 Suppl):Abstract nr IA02.