PIEZO1Deletion in CD11b+ Cells Suppresses Rhabdomyosarcoma Tumor Rejection and Generates a Tumor-Permissive Immune Landscape

Abstract

Abstract In several cancers, including the aggressive sarcoma, rhabdomyosarcoma (RMS), tumor-associated myeloid cells (TAMCs) are the largest immune populations and are correlated with poor survival outcomes. TAMCs are a mixed and ‘plastic’ population that can sense changes in their environment, including intra-tumoral ECM stiffness, and change their functioning accordingly. Despite the clinical influences these cells have and the detrimental effects that elevated tumor microenvironment (TME) stiffness has on immune cells’ phenotype, little is known about the proteins that sense and mediate these changes. We propose inhibition of mechanosensitive cation channel, PIEZO1, promotes a pro-tumor phenotype in TAMCs while its activation skews this population to anti-tumor functioning thereby enhancing tumor rejection.PIEZO1’s influence on tumor rejection was assessed by inoculating a novel murine CD11b-conditional homozygous PIEZO1 knockout strain with syngeneic RMS cells and performing several analyses. Tumor volume and survival analyses found that RMS-bearing CD11b-conditional PIEZO1 KO mice developed larger tumors and had diminished overall survival as compared to wild-type mice. Flow cytometric analysis of tumors revealed increased pro-tumor macrophage frequency in tumor and expansion of MDSCs in the TME and tumor-draining lymph node (TDLN). Interestingly, despite PIEZO1 KO tumors having increased T cells, they had lowerPD-1+ CD4 and CD8 T cell frequencies; a trend also observed in the spleen and TDLN. These findings suggest without PIEZO1 expression, TAMCs predominantly polarize to a ‘pro-tumor’ state, thereby preventing T cell and adaptive immune cells’ activation, leading to lower survival and increased tumor burden. NCI T32 (5T32CA059366-27)