Tumor-derived extracellular vesicles regulate tumor-infiltrating regulatory T cells via the inhibitory immunoreceptor CD300a
Tumor-derived extracellular vesicles regulate tumor-infiltrating regulatory T cells via the inhibitory immunoreceptor CD300a
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DOI：
10.1101/2020.11.10.376715
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发表时间：
2020-11
期刊：
影响因子：
7.7
通讯作者：
Y. Nakazawa;Kazumasa Kanemaru;C. Nakahashi-Oda;A. Shibuya
中科院分区：
文献类型：
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作者：
Y. Nakazawa;Kazumasa Kanemaru;C. Nakahashi-Oda;A. Shibuya
尽管肿瘤浸润调节性 T (Treg) 细胞在肿瘤免疫中发挥着关键作用，但肿瘤微环境中 Treg 细胞的激活如何受到调节仍不清楚。在这里，我们发现，与野生型小鼠相比，树突状细胞 (DC) 上缺乏抑制性免疫受体 CD300a 的小鼠在移植 B16 黑色素瘤后，肿瘤中的 Treg 细胞数量增加，肿瘤生长速度更快。细胞外囊泡 (EV) 释放的药理学损伤会减少 CD300a 缺陷小鼠中的 Treg 细胞数量。 DC 与肿瘤源性 EV (TEV) 共培养诱导 CD300a 内化并将 EV 掺入核内体，其中 CD300a 抑制 TEV 介导的 TLR3-TRIF 信号传导，从而激活 IFN-β-Treg 细胞轴。我们还表明，CD300A 的较高表达与黑色素瘤患者的肿瘤浸润 Treg 细胞减少和生存时间延长有关。我们的研究结果揭示了 TEV 和 CD300a 对 DC 在肿瘤微环境中 Treg 细胞激活中的作用。
Although tumor-infiltrating regulatory T (Treg) cells play a pivotal role in tumor immunity, how Treg cell activation are regulated in tumor microenvironments remains unclear. Here, we found that mice deficient in the inhibitory immunoreceptor CD300a on their dendritic cells (DCs) have increased numbers of Treg cells in tumors and greater tumor growth compared with wild-type mice after transplantation of B16 melanoma. Pharmacological impairment of extracellular vesicle (EV) release decreased Treg cell numbers in CD300a-deficient mice. Coculture of DCs with tumor-derived EV (TEV) induced the internalization of CD300a and the incorporation of EVs into endosomes, in which CD300a inhibited TEV-mediated TLR3-TRIF signaling for activation of the IFN-β-Treg cells axis. We also show that higher expression of CD300A was associated with decreased tumor-infiltrating Treg cells and longer survival time in patients with melanoma. Our findings reveal the role of TEV and CD300a on DCs in Treg cell activation in the tumor microenvironment.