Global Pannexin 1-deletion increases tumor-infiltrating lymphocytes in the BRAF/Pten mouse melanoma model

Abstract

ABSTRACTImmunotherapies for malignant melanoma seek to boost the anti-tumoral response of CD8+T cells but have a limited patient response rate, in part due to limited tumoral immune cell infiltration. Genetic or pharmacological inhibition of Pannexin 1 (PANX1) channel-forming protein is known to decrease melanoma cell tumorigenic propertiesin vitroandex vivo. Here, we crossedPanx1knockout (Panx1−/−) mice with the inducible melanoma model:BrafCA,PtenloxP,Tyr::CreERT2(BPC). We found that deleting thePanx1gene in mice does not reduce BRAF(V600E)/Pten-driven primary tumor formation or improve survival. However, BPC-Panx1−/-mice tumors exhibited a significant increase in infiltration of CD8+T lymphocytes with no changes in the expression of early T cell activation marker CD69, LAG-3 checkpoint receptor or PD-L1 in tumors when compared to BPC-Panx1+/+genotype. Our results suggest that although aPanx1deletion does not overturn the aggressiveBRAF/Pten-driven melanoma progressionin vivo, it does increase the infiltration of effector immune T cell populations in the tumor microenvironment. We propose that PANX1-targeted therapy could be explored as a strategy to increase tumor-infiltrating lymphocytes to boost anti-tumor immunity.