TGF-β通过miR-23a-3p/IRF1轴下调主要组织相容性复合体I类表达促进肝癌免疫逃逸

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The TGF- ⋅β /miR-23a-3p/IRF1 axis mediates immune escape of hepatocellular carcinoma by inhibiting major histocompatibility complex class I

YU Ying'，Li，ang，ONGueyi，HAOQianqian，NGiolo2 1Schooloficedilsieo

Abstract： Objective To investigate the mechanism by which transforming growth factor- β （TGF-β） regulates major histocompatibilityomplexclassI（MH-I）exprssoninhepatocellularcarcinoma （HCC）cellsanditsoleinimmuneevasion of HCC.Methods HCCcells treated with TGF-β aloneor incombination with SB-431542 （a TGF-β typeIreceptor inhibitor） wereexamined for changes in MHC-I expressionusingRT-qPCRand Western bloting.ARNA interference experiment was used to explore the role of miR-23a-3p/IRF1 signaling in TGF ⋅{β -mediatedregulation ofMHC-I.HCCcellswithdifferent treatmentswereco-culturedwith human peripheral blood mononuclearcells （PBMCs），and thechangesin HCC cell proliferationwasasessedusingCCK-8andcoonyformationasays.T-cellcytotoxicityintheco-culture systemswasassessed withlactatedehydrogenase （LDH）releaseand JC-1mitochondrial membrane potentialassays，and T-cellactivation was evaluated by flow cytometric analysis of CD69 cellsand ELISA for TNF- α secretion. Results TGF β treatment significantly suppressedMH-IexpessioninHCCcellsandreduced-cellactivation，leadingtoicreasedtumorcellproliferatioan decreased HCC cell death in the co-culture systems. Mechanistically， TGF- β upregulated miR-23a-3p，which directly targeted IRF1 to inhibit MHC-I transcription. Overexpression of miR-23a-3p phenocopied TGF- β -induced suppression of IRF1 and MHC-I. Conclusion We reveal a novel immune escape mechanism of HCC，inwhich TGF- ⋅β attenuatesTcell-mediated antitumor immunity by suppressing MHC-I expression through the miR-23a-3p/IRF1 signaling axis.

Keywords： livercancercels; transforminggrowth factor-β; majorhistocompatibilitycomplexclassI; tumor immune escape

肝癌是全球第6大常见癌症，也是癌症相关死亡的第2大原因，肝癌的发生和进展是一个复杂的过程，免疫治疗已成为肝癌治疗的重要手段之一[12]。（剩余18486字）