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 (Treg) 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 CD25loPD-1hi phenotype. Together, our results suggest that Piezo1 optimizes T cell activation in the context of a tumor response.
Acknowledgments
We thank IceCure Medical, Ltd. for providing the ProSense CryoSurgical System, Saada Eid for genotyping of mice, and David Askew for manuscript editing. The authors acknowledge support from the Center for Pediatric Immunotherapy at the Angie Fowler AYA Cancer Institute, UH Rainbow Babies & Children’s Hospital. M.A. is supported by Qassim University, Qassim, Saudi Arabia, for the Ph.D. scholarship. A.Y.H. is supported as a fellow of the Harrington Discovery Institute and an endowed chair from the Theresia G. & Stuart F. Kline Family Foundation. Graphs 1A, 3A, 5A, and 6A were created using Biorender.com.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Author contributions
Conceptualization, m.a. and A.Y.H.; formal analysis, m.a. and A.Y.H.; resources, A.Y.H.; data curation, m.a., M.A., M.B., J.M., B.-G. K., S.L.T., A.S., D.K., S.-H. C.; writing – original draft preparation, m.a.; writing – review and editing, m.a., A.Y.H.; visualization, m.a., A.Y.H.; supervision, A.Y.H.; project administration, m.a., A.Y.H.; funding acquisition, m.a., A.Y.H. All authors have read and agreed to the published version of the manuscript.
Classification
Immunology and Inflammation
Data availability statement
The authors confirm that the data supporting the findings of this study are available within the article and its supplementary materials. The reagents are available from the corresponding author, A.Y.H., upon reasonable request and full execution of a Material Transfer Agreement agreed to by both parties.
Supplementary material
Supplemental data for this article can be accessed online at https://doi.org/10.1080/2162402X.2023.2281179