UC San Diego

CD8+ tumor infiltrating lymphocytes (TILs) can selectively detect and destroy cancer cells. This requires ligation of the TCR and co-stimulatory CD28, which induces a transcriptional program driven by several key transcription factors, including nuclear factor of activated T cells (NFAT), activator protein 1 (AP-1), and nuclear factor kappa light chain enhancer of activated of B cells (NF κB). In the solid tumor microenvironment, effective antitumor responses are thwarted by chronic TCR stimulation of TILs without adequate co-stimulatory signals, resulting in the suboptimal activity of AP-1 and NF κB, and a dysfunctional state known as exhaustion. Exhausted TILs fail to reject tumors and are characterized by the upregulation of multiple inhibitory receptors, loss of effector function, and unique epigenetic and transcriptional programs distinct from effector and memory T cells. We hypothesized that restoring optimal levels of AP-1 and NF κB transcription factors in CD8+ TILs could counteract exhaustion. Using gain-of-function and loss-of-function screens, we discovered BATF and RelB act to positively and negatively regulate the exhaustion program in CD8+ TILs, respectively. Enforced expression of BATF reversed aspects of exhaustion, restored effector function, and favored memory formation, while depletion of RelB induced the proliferation of TILs, conferred greater antitumor activity, and prolonged the survival of tumor-bearing mice. These results highlight the importance of maintaining optimal levels of bZIP and NF κB transcription factors in TILs and demonstrate that manipulating these factors can improve immune responses against tumors.