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肿瘤来源的细胞外囊泡通过抑制性免疫受体 CD300a 调节肿瘤浸润调节性 T 细胞。

Tumor-derived extracellular vesicles regulate tumor-infiltrating regulatory T cells via the inhibitory immunoreceptor CD300a.

机构信息

Department of Immunology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.

Doctoral Program of Biomedical Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Japan.

出版信息

Elife. 2021 Nov 9;10:e61999. doi: 10.7554/eLife.61999.

DOI:10.7554/eLife.61999
PMID:34751648
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8577836/
Abstract

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.

摘要

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 Treg 细胞在肿瘤微环境中的激活如何调节仍不清楚。在这里，我们发现树突状细胞（DC）中抑制性免疫受体 CD300a 缺失的小鼠在移植 B16 黑色素瘤后，肿瘤中的 Treg 细胞数量增加，肿瘤生长速度加快。药物抑制细胞外囊泡（EV）的释放会减少 CD300a 缺陷小鼠中的 Treg 细胞数量。DC 与肿瘤衍生的 EV（TEV）共培养会诱导 CD300a 的内化和 EV 进入内体，其中 CD300a 抑制 TEV 介导的 TLR3-TRIF 信号通路，激活 IFN-β-Treg 细胞轴。我们还表明，黑色素瘤患者中 CD300A 的高表达与肿瘤浸润性 Treg 细胞减少和生存时间延长有关。我们的发现揭示了 TEV 和 DC 上的 CD300a 在肿瘤微环境中 Treg 细胞激活中的作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bf0d/8577836/4c1858b5c17d/elife-61999-fig7.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bf0d/8577836/4c1858b5c17d/elife-61999-fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bf0d/8577836/e766a51fc9d5/elife-61999-fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bf0d/8577836/3e946fbc4ff6/elife-61999-fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bf0d/8577836/43c5081fae78/elife-61999-fig2-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bf0d/8577836/0822cf979004/elife-61999-fig2-figsupp2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bf0d/8577836/de0ebb087581/elife-61999-fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bf0d/8577836/c1cd19ad9f36/elife-61999-fig3-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bf0d/8577836/d1cc6362ebd2/elife-61999-fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bf0d/8577836/3a832dd5e189/elife-61999-fig4-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bf0d/8577836/4fa92f218d06/elife-61999-fig5.jpg
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