Pannexin-1 promotes CD8+ T cell antitumor immunity against colorectal cancer in a gender-dependent way 2256739

Abstract

Colorectal cancer (CRC) is the second leading cause of cancer death in the U.S., with stage IV patients showing poor five-year survival. Immune checkpoint blockade shows limited efficacy in CRC, highlighting the need to better understand how CD8+ T cells are regulated by the tumor microenvironment (TME). In the TME, CD8+ T cells often become exhausted and lose cytotoxic function. Terminally exhausted cells express high inhibitory receptors, PD-1, Tim-3, and low proliferative capacity; whereas stem-like exhausted cells can self-renew and respond well to checkpoint blockade. Metabolic regulation is critical for CD8+ T cells, including membrane channels that export metabolites. Our lab studies Pannexin-1 (PANX1), a channel that exports ATP and promotes memory CD8+ T cell survival via AMPK signaling. We found that PANX1 is crucial for effective antitumor CD8+ T cell responses in CRC. High PANX1 expression correlates with increased CD8+ T cell infiltration and better prognosis in stage IV CRC patients. Using CRC mouse models, CD8-specific Panx1 knockout males, but not females, fail to control MC38 tumors, with tumor-infiltrating CD8+ T cells showing higher exhaustion, fewer stem-like cells in lymph nodes, and lower AMPK activity. Single-cell RNAseq and InfinityFlow confirm enhanced exhaustion signatures in PANX1-KO tumor-infiltrating stem-like exhausted cells, while wild-type tumors accumulate more effector-like (Zeb2+) CD8+T cells. Preliminary data suggests that AMPK overactivation (AICAR) significantly restores PANX1-KO exhausted CD8+ T cells. Finally, the gender-specific discrepancies may involve androgen receptor signaling, elevated in PANX1-KO exhausted cells. Ongoing studies examine whether PANX1-mediated AMPK activity regulates androgen receptor expression. Together, these findings suggest PANX1 promotes CD8+T cell-driven anti-tumor immunity in CRC in a gender-dependent manner, potentially explaining sex-based differences. n/a Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)