Specific Decrease in B-Cell-Derived Extracellular Vesicles Enhances Post-Chemotherapeutic CD8+ T Cell Responses
Specific Decrease in B-Cell-Derived Extracellular Vesicles Enhances Post-Chemotherapeutic CD8+ T Cell Responses
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B 细胞来源的细胞外囊泡的特异性减少增强化疗后 CD8( ) T 细胞反应
DOI：
10.1016/j.immuni.2019.01.010
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发表时间：
2019-03-19
期刊：
影响因子：
32.4
通讯作者：
Cai, Zhijian
中科院分区：
文献类型：
--
作者：
Zhang, Fanghui;Li, Rongrong;Cai, Zhijian
全身免疫抑制严重影响化疗的抗肿瘤效果。在这里，我们发现来自B细胞的CD 19（+）细胞外囊泡（EV）通过CD 39和CD 73囊泡结合蛋白将来自化疗处理的肿瘤细胞的ATP水解为腺苷，从而损害CD 8（+）T细胞应答。在荷瘤小鼠和患者中，血清CD 19（+）EVs增加。血清CD 19 + EVs较少的患者化疗后预后较好。缺氧诱导因子-1 α（HIF-1 α）通过诱导Rab 27 a mRNA的转录，促进B细胞释放CD 19（+）EVs。B细胞中Rab 27 a或HIF-1 α的缺陷抑制了CD 19（+）EV的产生并提高了化疗抗肿瘤效果。通过携带Rab 27 a siRNA的灭活EB病毒沉默B细胞中的Rab 27 a大大提高了人源化免疫受损NOD Prkdc（scid）Il 2 rg（-/-）小鼠中的化疗功效。因此，减少CD 19（+）EV具有提高化疗抗肿瘤作用的高潜力。
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-1 alpha (HIF-1 alpha) promoted B cells to release CD19(+) EVs by inducing Rab27a mRNA transcription. Rab27a or HIF-1 alpha 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 Prkdc(scid) Il2rg(-/-) mice. Thus, decreasing CD19(+) EVs holds high potential to improve the chemotherapeutic antitumor effect.