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Specific Decrease in B-Cell-Derived Extracellular Vesicles Enhances Post-Chemotherapeutic CD8+ T Cell Responses
Immunity ( IF 25.5 ) Pub Date : 2019-02-12 , DOI: 10.1016/j.immuni.2019.01.010
Fanghui Zhang , Rongrong Li , Yunshan Yang , Chunhui Shi , Yingying Shen , Chaojie Lu , Yinghu Chen , Wu Zhou , Aifu Lin , Lei Yu , Wanjing Zhang , Zhenwei Xue , Jianli Wang , Zhijian Cai

Systemic immunosuppression greatly affects the chemotherapeutic antitumor effect. Here, we showed that CD19+ extracellular vesicles (EVs) from B cells through CD39 and CD73 vesicle-incorporated proteins hydrolyzed ATP from chemotherapy-treated tumor cells into adenosine, thus impairing CD8+ T cell responses. Serum CD19+ EVs were increased in tumor-bearing mice and patients. Patients with fewer serum CD19+ EVs had a better prognosis after chemotherapy. Upregulated hypoxia-inducible factor-1α (HIF-1α) promoted B cells to release CD19+ EVs by inducing Rab27a mRNA transcription. Rab27a or HIF-1α deficiency in B cells inhibited CD19+ EV production and improved the chemotherapeutic antitumor effect. Silencing of Rab27a in B cells by inactivated Epstein-Barr viruses carrying Rab27a siRNA greatly improved chemotherapeutic efficacy in humanized immunocompromised NOD Prkdcscid Il2rg−/− mice. Thus, decreasing CD19+ EVs holds high potential to improve the chemotherapeutic antitumor effect.



中文翻译:

B细胞衍生的胞外小泡中的特定减少增强了化疗后CD8 + T细胞的反应。

全身免疫抑制极大地影响化学疗法的抗肿瘤作用。在这里,我们显示了B细胞通过CD39和CD73囊泡结合的CD19 +细胞外囊泡(EVs)将ATP从化疗后的肿瘤细胞中水解为腺苷,从而削弱了CD8 + T细胞的反应。荷瘤小鼠和患者的血清CD19 + EV升高。血清CD19 + EV较少的患者在化疗后预后较好。缺氧诱导因子-1α(HIF-1α)上调通过诱导Rab27a mRNA转录促进B细胞释放CD19 + EV 。B细胞中Rab27a或HIF-1α缺乏抑制CD19 +电动汽车的生产和改善了化学疗法的抗肿瘤作用。通过进行灭活爱泼斯坦-巴尔病毒的B细胞的Rab27a沉默Rab27a的siRNA大大提高化疗的功效在人源化免疫受损NOD PRKDC SCID 的II2rg / - -小鼠。因此,减少CD19 + EVs具有提高化疗抗肿瘤作用的高潜力。

更新日期:2019-02-12
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