Extracellular vesicles derived from M2-polarized tumor-associated macrophages promote immune escape in ovarian cancer through NEAT1/miR-101-3p/ZEB1/PD-L1 axis.

Abstract

Evidence has been presented demonstrating that CD8+ T cells confer anti-cancer effects, which offers a promising approach to enhance immunotherapy. M2-polarized tumor-associated macrophages (TAMs) could transfer RNA to cancer cells by secreting extracellular vesicles (EVs) and stimulate immune escape of cancer cells. Thus, the current study aimed at exploring how EVs derived from M2-polarized TAMs (M2-TAMs) affected the proliferation of ovarian cancer (OC) cells and apoptosis of CD8+ T cells. M2-TAMs were observed in OC tissues, which promoted proliferation of OC cells and CD8+ T cell apoptosis by secreting EVs. OC-associated differentially expressed gene NEAT1 was screened by bioinformatics analysis. The in vitro and in vivo effects of TAM-EVs-NEAT1 and its regulatory mechanism were assessed using gain- and loss-of-function assays in co-culture systems of TAMs-derived EVs, OC cells, and CD8+ T cells and in tumor-bearing mice. NEAT1 was highly expressed in M2-derived EVs and OC cells co-cultured with M2-derived EVs. NEAT1 sponged miR-101-3p to increase ZEB1 and PD-L1 expression. In vitro and in vivo assays confirmed the tumor-supporting effects of NEAT1 delivered by M2-derived EVs on OC cell proliferation and CD8+ T cell apoptosis as well as tumor growth. Collectively, M2-derived EVs containing NEAT1 exerted a tumor-promoting role in OC via the miR-101-3p/ZEB1/PD-L1 axis.