IDDF2021-ABS-0158 Small extracellular vesicles derived from esophageal squamous cell carcinoma promote immunosuppressive effects of myeloid-derived suppressor cells after ionizing radiation

Background Radiation therapy is effective in achieving local control in esophageal squamous cell carcinoma(ESCC), yet there is evidence to suggest that changes in the tumour micro-environment induced by radiation can also promote metastasis. We investigated if ionizing radiation is capable of promoting immunosuppressive effects of myeloid-derived suppressor cells(MDSCs) through ESCC-derived small extracellular vesicles(sEVs). Methods PBMCs from healthy donors were cocultured with sEVs derived from ESCC cell lines before and after radiation. The proportion of MDSCs and their immunosuppressive function were analysed. ESCC were induced by 4-nitroquinoline-1-oxide (4NQO) in C57BL/6 mice. The MDSC proportion and function of ESCC bearing mice were analyzed and RNA-seq was performed in MDSCs before and after radiation. sEVs from the plasma of ESCC-bearing mice before and after radiation was isolated and injected into healthy C57BL/6 mice to investigate their effects to MDSCs. Small RNA-seq of sEVs derived from Kyse 30 before and after radiation was performed. The function of changed microRNAs in sEVs was verified in vitro, and its targeting pathways were also investigated. Results sEVs derived from radiated cells exhibited a stronger MDSCs induction capacity and MDSCs were more suppressive of T cell proliferation. MDSCs in ESCC bearing mice after radiation increased and the suppressive effect of MDSCs was improved. RNA-seq showed up-regulated PI3K-AKT pathway activity in MDSCs in ESCC bearing mice after radiation. sEVs from the plasma of ESCC-bearing mice after radiation-induced more MDSCs and had a stronger ability to induce immunosuppressive function of MDSCs. miRNA-26b in sEVs of ESCC cell lines and plasma of tumour-bearing mice were found to be up-regulated after radiation. miRNA-26b was found to have the ability to induce MDSCs expansion and function. miRNA-26b was found to activate PI3K-AKT pathway through targeting Pten. Conclusions sEVs from ESCC cells after ionizing radiation had a stronger ability to induce MDSCs than sEVs 0gy in both promoting cell expansion and immunosuppressive function. In vivo study validated the MDSC-inducing function of radiation.