Exosomal PD-L1 induces MDSCs accumulation through IL-6/STAT3 pathway in gastric cancer

Abstract Background. Myeloid-derived suppressor cells (MDSCs) are the major factor in gastric cancer (GC) immune evasion. Nevertheless, the molecular process behind the expansion of MDSCs brought by tumor-derived exosomes (TDEs) remains elusive. Methods. Ninety GC patients had their levels of exosomal and soluble PD-L1 examined using the enzyme-linked immunosorbent test (ELISA) to determine their prognostic value. To investigate the correlation between exosomal PD-L1 and MDSCs, the percentage of MDSCs in the peripheral blood of 57 GC patients was assessed by flow cytometry. Through the application of ultracentrifugation, exosomes were separated from the GC cell supernatant and detected via Western blotting, NTA, and transmission electron microscopy (TEM). The function of exosomal PD-L1 in MDSCs was evaluated using immunofluorescence, western blotting and flow cytometry in GC cells-derived xenograft (CDX) model. Results. The overall survival (OS) of GC patients in the high exosomal PD-L1 group was significantly lower than that in the low exosomal PD-L1 group, however, there was no a significant correlation between soluble PD-L1 and OS in GC patients. Furthermore, we found that the expression of exosomal PD-L1 was positively correlated with the proportion of polymorphonuclear MDSCs (PMN-MDSCs, r = 0.4944, P < 0.001) and monocytic MDSCs (M-MDSCs, r = 0.3663, P = 0.005) in GC patients, indicating that exosomal PD-L1 might induce immune suppression by promoting the aggregation of MDSCs. In addition, we found that exosomal PD-L1 might stimulate MDSC proliferation by triggering the IL-6/STAT3 signaling pathway in vitro. The CDX model confirmed that exosomal PD-L1 could stimulate tumor development and MDSC amplification. Conclusions. Exosomal PD-L1 is linked to a poor prognosis for GC patients, which is due to the stronger activation to MDSCs by exosomal PD-L1 through the IL-6/STAT3 signaling pathway.