Rasal1 regulates stemness and exhaustion of CD8 T-cells for more effective anti-PD-1 tumor immunity 3588

Abstract Description Rasal1, a GTPase-activating protein (GAP) that interacts with the T-cell receptor (TCR), inhibits the activation of ZAP-70 and the p21ras-ERK signaling pathways in T cells. Despite the success of anti-PD-1 immune checkpoint blockade (ICB), the underlying intracellular pathways that influence its effectiveness are unclear. In this study, we reveal that Rasal1 is a novel intracellular checkpoint regulator, influencing the stemness and exhaustion of tumor-infiltrating lymphocytes (TILs) in tumor immunity. Mice with a loss-of-function Rasal1c-mut showed altered cellularity of the thymus and peripheral CD4+ and CD8+ T cells. Concomitantly, these mice exhibited a greater ability to control tumor growth, which correlated with an increased presence of CD8+effector-memory TILs. Further, investigations revealed that Rasal1c-mut T cells displayed hyperactivated ZAP-70 and ERK1/2 signaling pathways, coupled with an increase in the mitochondrial-based oxidative phosphorylation pathway in T-cells. Further, surprisingly, the combination of anti-PD-1 blockade with Rasal1c-mut exhibited a synergistic effect in controlling tumor growth. This effect was associated with a reduction in T-cell exhaustion and the emergence of self-replicating TCF1+ stem-like CD8+ TILs. Collectively, our study emphasizes the critical role of Rasal1 in cooperating with anti-PD-1 blockade to limit T-cell exhaustion and generate stem-like TILs, thereby promoting more effective anti-tumor immunity. Funding Sources Canadian Institutes of Health Research Foundation grant (159912) Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)