Estrogen inhibits the growth of colon cancer in mice through reversing extracellular vesicle-mediated immunosuppressive tumor microenvironment

Postmenopausal women taking estrogen supplements are at a lower risk of advanced colorectal cancer, but the underlying mechanism remains unclear. Thus, this study examined the role of estrogen in colorectal cancer. Estrogen receptor expression levels in in situ colorectal cancer tissue from female patients increased significantly, indicating their estrogen sensitivity. Compared with the sham-operated group, the growth of MC38 tumors was enhanced in ovariectomized mice, which was reversed in ovariectomized mice with E2 supplementation. The PD-L1+ M2-like macrophage, regulatory T (Treg) cell, and myeloid-derived suppressor cell (MDSC) populations significantly increased, and the population of cytotoxic CD8+ T cells declined in MC38 tumors in ovariectomized mice, which were all reversed in ovariectomized mice with E2 supplementation. MC38 cell-derived extracellular vesicles (MC38-EVs), but not EVs derived from MC38 cells treated with E2 (E2-MC38-EVs), were involved in the establishment of immunosuppressive tumor microenvironment. E2-MC38-EVs contained lower TGF-β1 levels and were less capable of inducing Treg cells than MC38-EVs in vitro. Overall, these results show that estrogen treatment prevents MC38 tumor growth via regulating the tumor immune microenvironment through MC38-EVs.