Cancer-associated fibroblasts induced by colorectal cancer cells inhibit γδT cells killing function through the ERK/COX-2/PGE2 pathways

Abstract

Abstract The tumor microenvironment (TME) is a highly ordered ecosystem in which several non-malignant cell types, including immune cells, cancer-associated fibroblasts (CAFs), and other cell types, are encircled by cancer cells. Colorectal cancer (CRC) is determined by the reciprocal contact between cancer cells and host cells. γδT cells represent a significant subset of the natural immune system and are vital in the battle against CRC. Yet, the ability of γδT cells to kill is limited in the CRC microenvironment. The purpose of this work is to investigate how CRC cells-induced CAFs affect γδT cells, which offers fresh perspectives on how to broaden CRC treatment approaches. The findings demonstrated that fibroblast activation, proliferation, and clone formation were induced by CRC cell culture supernatants via the ERK signaling pathway. On the basis of analyzing the correlation between γδT cells and CAFs, we further demonstrated that the generated CAFs can inhibit the killing function of γδT cells to CRC cells. In CAFs co-cultured with γδT cells, ERK inhibitors can decrease the expression levels of COX-2 and PGE2, and partially reverse the inhibition of CAFs on γδT cell killing function. According to our research, CAFs generated by CRC cells in the TME may decrease the ability of γδT cells to destroy themselves and facilitate the development of an immunosuppressive microenvironment by activating the ERK/COX-2/PGE2 pathway. They establish the groundwork for assessing how ERK inhibitors alleviate γδT cell immune suppression in the CRC microenvironment, investigating novel targets for CRC therapy, and formulating clinical CRC treatment plans.