Tumor-derived extracellular vesicles containing microRNA-1290 promote immune escape of cancer cells through the Grhl2/ZEB1/PD-L1 axis in gastric cancer

Gastric cancer (GC) is a highly prevalent malignancy featured by dismal oncological outcomes. Accumulating pieces of evidence have consensus over the therapeutic significance of extracellular vesicles (EVs) and its role in carcinogenesis. Here, we planned to uncover EVs? role in GC by shuttling microRNA-1290 (miR1290) and to identify the possible molecular mechanism associated with Grhl2, PD L1, and ZEB1. Grhl2 was under-expressed in GC tissues, exhibiting a negative correlation with PD-L1 expression. In addition, Grhl2 promoted T cell proliferation by down-regulating PD-L1 via inhibiting ZEB1, while miR-1290 was found to negatively regulate Grhl2. EVs were also isolated from GC cells or normal gastric epithelial cells and identified with the presence of EV markers. miR-1290 expression was determined to be enriched in the EVs derived from GC cells and observed to promote the suppressive action of GC cells on T cell activation by up-regulating PD-L1 via the Grhl2/ZEB1 pathway in the co-culture system of GC cells with or without treatment of EVs with T cells. Moreover, we also developed a mouse model of GC and injected the EVs derived from miR-1290-inhibitor-treated GC cells into the tumor bearing mice for further validation of mechanism in vivo. Intriguingly, the pivotal role of EVs-shuttled miR-1290 as an oncomiR was demonstrated in vivo. Collectively, we found that miR-1290 in EVs secreted from GC cells contributed to immune escape through the Grhl2/ZEB1/PD-L1 axis. (Translational Research 2021; 231:102-112) Abbreviation: GC = gastric cancer; EVs = extracellular vesicles; miR-1290 = microRNA-1290; Grhl2 = grainy head-like 2; ZEB1 = zinc finger E-box binding homeobox transcription factor 1; PD-L1 = programmed death ligand 1; PD-1 = programmed death 1; NC = negative control; sh = shRNA; OE = over-expression; RT-qPCR = real time quantitative PCR; IHC = immunohistochemistry; TIL = tumor-infiltrating lymphocyte