Piezo1 facilitates optimal T cell activation during tumor challenge

Abstract

Functional effector T cells in the tumor microenvironment (TME) are critical for successful anti-tumor responses. T cell anti-tumor function is dependent on their ability to differentiate from a naïve state, infiltrate into the tumor site, and exert cytotoxic functions. The factors dictating whether a particular T cell can successfully undergo these processes during tumor challenge are not yet completely understood. Piezo1 is a mechanosensitive cation channel with high expression on both CD4⁺ and CD8⁺ T cells. Previous studies have demonstrated that Piezo1 optimizes T cell activation and restrains the CD4⁺ regulatory T cell (T_reg) pool in vitro and under inflammatory conditions in vivo. However, little is known about the role Piezo1 plays on CD4⁺ and CD8⁺ T cells in cancer. We hypothesized that disruption of Piezo1 on T cells impairs anti-tumor immunity in vivo by hindering inflammatory T cell responses. We challenged mice with T cell Piezo1 deletion (P1KO) with tumor models dependent on T cells for immune rejection. P1KO mice had the more aggressive tumors, higher tumor growth rates and were unresponsive to immune-mediated therapeutic interventions. We observed a decreased CD4:CD8 ratio in both the secondary lymphoid organs and TME of P1KO mice that correlated inversely with tumor size. Poor CD4⁺ helper T cell responses underpinned the immunodeficient phenotype of P1KO mice. Wild type CD8⁺ T cells are sub-optimally activated in vivo with P1KO CD4⁺ T cells, taking on a CD25^loPD-1^hi phenotype. Together, our results suggest that Piezo1 optimizes T cell activation in the context of a tumor response.

Keywords: Cancer immunology; Piezo1; T cell mechanobiology; rhabdomyosarcoma.