Dendritic cell Piezo1 integrating mechanical stiffness and inflammatory signals directs the differentiation of TH1 and Treg cells in cancer

Abstract

Dendritic cells (DCs) play an important role in anti-tumor immunity by inducing T cell differentiation. Herein, we found that the mechanical sensor Piezo1 expressed by DCs integrates innate inflammatory stimuli and stiffness signals and directs the reciprocal differentiation of TH1 and regulatory T (Treg) cells in cancer. Genetic deletion of Piezo1 in DCs inhibited the generation of TH1 cells while driving the development of Treg cells in promoting cancer growth. Mechanistically, Piezo1-deficient DCs regulated the secretion of the polarizing cytokines TGF{beta}1 and IL-12, leading to increased TGF{beta}R2-p-Smad3 activity and decreased IL-12R{beta}2-p-STAT4 activity while inducing the reciprocal differentiation of Treg and TH1 cells. In addition, Piezo1 integrated the SIRT1-hypoxia-inducible factor-1 alpha (HIF1)-dependent metabolic pathway and calcium-calcineurin-NFAT signaling pathway to orchestrate reciprocal TH1 and Treg lineage commitment through DC-derived IL-12 and TGF{beta}1. Our studies provide critical insight for understanding the role of the DC-based mechanical regulation of immunopathology in directing T cell lineage commitment in tumor microenvironments.