PAR2 deficiency enhances myeloid cell-mediated immunosuppression and promotes colitis-associated tumorigenesis

Protease-activated receptor 2 (PAR2) is a member of G-protein coupled receptors, which is widely expressed in intestinal epithelium and immune cells and plays critical roles in intestinal homeostasis. Activation of PAR2 has been implicated in inflammatory process and carcinogenesis. However, it remains unclear whether and how endogenous PAR2 affects colorectal tumorigenesis. Here, we found that PAR2 expression was enhanced in patients with inflammatory bowel disease and colorectal cancer. Intriguingly, PAR2 deficiency significantly aggravated colitis and promoted tumor development in AOM/DSS model. This finding was accompanied with upregulated pro-inflammatory factors IL-6, TNFα, COX2 and NOS2 in tumors of Par2^-/- mice. Moreover, PAR2 deficiency reshaped the tumor microenvironment through accumulation of tumor-promoting myeloid cells including tumor-associated macrophages and myeloid-derived suppressor cells (MDSCs) and reduction of anti-tumor T cells, which established an immunosuppressive microenvironment and facilitated tumor progression. Mechanistically, absence of PAR2 in MDSCs directly enhanced their immunosuppressive activity by promoting STAT3-mediated reactive oxygen species production. Our study reveals an unrecognized role of PAR2 in limiting colorectal carcinogenesis by regulating the tumor microenvironment. Specifically targeting PAR2 may be a potential alternative for colorectal cancer immunotherapy.