Zhang Ju, Liu Jiatao, Ni Jing, Lin Xiao, Fan Lulu, Sun Guoping
Department of Clinical Laboratory, Division of Life Sciences and Medicine, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei, Anhui, China.
Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui, China.
Inflammation. 2024 Dec 23. doi: 10.1007/s10753-024-02214-z.
Endoplasmic reticulum stress (ERs) is implicated in antitumor immunity. However, the exact role of ERs in mediating the effects of dendritic cells (DCs) is not unclear. In this study, we explored the role of exosomes derived from ER-stressed hepatocellular carcinoma (HCC) cells in the antitumor effects of DCs and the precise underlying mechanism. We found that ER-stressed HCC cells secreted more exosomes (EXO-TM) than those without ER stress (EXO-CON) and that exosomes were effectively taken up by DCs. EXO-TM significantly promoted DCs maturation, as demonstrated by the increased expression of HLA-ABC, CD83, CD80, CD86, and pro-inflammatory cytokines and the decreased expression of IL-10. Moreover, EXO-TM pulsed DCs (DC) significantly enhanced T lymphocyte-mediated lysis against several types of tumor cells by promoting the proliferation of CD3CD8 T cells and increasing the expression of INF-γ both in vitro and in vivo. Mechanistically, we found that heat shock protein (HSP) 90 was more significantly enriched in EXO-TM than in EXO-CON cells, and the knockdown of HSP90 remarkably reversed EXO-TM-mediated DC activation. Our results suggest that exosomes derived from ER-stressed HCC cells could enhance the antitumor effect of DC-mediated T lymphocytes, which may be related to the large amount of HSP90 carried in the exosomes. Therefore, regulating the HSP90 carrying capacity of tumor exosomes may be an effective immunotherapy strategy.
内质网应激（ERs）与抗肿瘤免疫有关。然而，ERs在介导树突状细胞（DCs）效应中的具体作用尚不清楚。在本研究中，我们探讨了内质网应激的肝癌（HCC）细胞来源的外泌体在DCs抗肿瘤效应中的作用及其确切的潜在机制。我们发现，内质网应激的HCC细胞比无内质网应激的细胞分泌更多的外泌体（EXO-TM），并且外泌体能够被DCs有效摄取。EXO-TM显著促进DCs成熟，表现为HLA-ABC、CD83、CD80、CD86和促炎细胞因子表达增加以及IL-10表达降低。此外，EXO-TM脉冲DCs（DC）通过促进CD3CD8 T细胞增殖和增加体外及体内INF-γ表达，显著增强T淋巴细胞介导的对几种肿瘤细胞的杀伤作用。机制上，我们发现热休克蛋白（HSP）90在EXO-TM中比在EXO-CON细胞中更显著富集，并且敲低HSP90可显著逆转EXO-TM介导的DC激活。我们的结果表明，内质网应激的HCC细胞来源的外泌体可增强DC介导的T淋巴细胞的抗肿瘤作用，这可能与外泌体中携带的大量HSP90有关。因此，调节肿瘤外泌体的HSP90携带能力可能是一种有效的免疫治疗策略。
