The eATP-exporting channel Pannexin-1 promotes CD8+ T cell responses to colorectal cancer 3754

Abstract Description Colorectal cancer (CRC) remains a significant global health burden, affecting millions of people every year. Despite recent advances, immunotherapies still face limited success against CRC, partly due to our incomplete understanding about how CRC induces CD8+ T cell exhaustion and which intracellular metabolic pathways can be leveraged to favor CD8+ T cell responses to CRC. CD8+ T cells express membrane-bound channels that can export metabolites, such as Pannexin-1 (PANX1). Panx1 exports ATP to the extracellular environment and has been shown, in our previous work, to promote the survival of memory CD8+ T cells through upregulation of the AMPK pathway. Notably, high PANX1 expression is associated with CD8+ T cell infiltration and better prognosis in stage IV CRC patients. Here, we show that PANX1 is essential for the induction of protective CD8+ T cell responses to CRC. PANX1-KO mice fail to control MC38 CRC tumors, had decreased numbers of antigen-specific tumor CD8+ T cells and increased expression of terminal exhaustion markers such as Tim-3. The defect in tumor CD8+ T cell accumulation is cell-intrinsic, as revealed by WT/PANX1-KO co-adoptive transfer experiments. We also found that intratumoral CD8+ T cells with better ability to respond to immunotherapy had increased AMPK activation. We are currently investigating whether PANX1 is necessary for CD8+ T cell AMPK activation inside tumors, and how PANX1 affects CD8+ T cells response to immunotherapy in the context of CRC. Funding Sources NIH AI139381 (R00) Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)