Tumor Endothelial Cell–Mediated Antigen-Specific T-cell Suppression via the PD-1/PD-L1 Pathway
Tumor Endothelial Cell–Mediated Antigen-Specific T-cell Suppression via the PD-1/PD-L1 Pathway
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DOI：
10.1158/1541-7786.mcr-19-0897
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发表时间：
2020-06
影响因子：
5.2
通讯作者：
K. Taguchi;T. Onoe;Tomoaki Yoshida;Y. Yamashita;Yuka Tanaka;H. Ohdan
中科院分区：
文献类型：
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作者：
K. Taguchi;T. Onoe;Tomoaki Yoshida;Y. Yamashita;Yuka Tanaka;H. Ohdan
肿瘤内皮细胞（TEC）在血管结构和生理学的区域特化中发挥多种作用。由于肿瘤微环境中的TEC与循环免疫细胞接触，它们不仅可能影响运输，而且可能影响抗肿瘤细胞免疫应答。在B16黑色素瘤细胞的小鼠肿瘤植入模型中，TEC表达MHC II类、共刺激分子和程序性死亡配体1（PD-L1），表明它们是具有抑制活性的抗原（Ag）呈递细胞。此外，TEC能够摄取并呈递肿瘤来源的卵清蛋白（OVA）肽在MHC I类分子上。在功能测定中，相对于B16肿瘤衍生的TEC，B16-OVA肿瘤衍生的TEC显著抑制OVA特异性CD 8 + T细胞的增殖和Ag特异性细胞毒性。这种抑制活性需要细胞-细胞接触，并通过PD-L1阻断而消除。TEC损害CD 8 + T细胞的促炎细胞因子产生，包括IL 2、TNFα和IFNγ。B16-OVA肿瘤衍生的TEC诱导免疫抑制性CD 4 + T细胞，其通过抑制性细胞因子（包括IL 10和TGFβ）抑制OVA特异性CD 8 + T细胞增殖。TEC中PD-L1缺乏，但造血细胞中没有，削弱了肿瘤浸润性CD 8 + T细胞的抑制和凋亡，导致体内模型中肿瘤发展的抑制。这些数据表明，TEC可能通过PD-1/PD-L1途径调节肿瘤Ag特异性CD 8 + T细胞的免疫应答，并以Ag特异性方式诱导免疫抑制性CD 4 + T细胞，从而有助于肿瘤免疫逃避。意义：这项研究的结果可能会鼓励进一步开发新的抗癌疗法和策略。
Tumor endothelial cells (TEC) play multiple roles in the regional specialization of vascular structure and physiology. Because TECs in the tumor microenvironment come in contact with circulating immune cells, they might influence not only trafficking but also the antitumor cellular immune response. In a mouse tumor implantation model with B16 melanoma cells, TECs expressed MHC class II, costimulating molecules, and programmed death-ligand 1 (PD-L1), suggesting that they are antigen (Ag)-presenting cells with suppressive activity. Furthermore, TECs were able to take up and present tumor-derived ovalbumin (OVA) peptide on MHC class I molecules. In functional assays, B16-OVA tumor–derived TECs significantly suppressed the proliferation and Ag-specific cytotoxicity of OVA-specific CD8+ T cells relative to those of B16 tumor–derived TECs. This suppressive activity required cell–cell contact and was abrogated by PD-L1 blockade. TECs impaired proinflammatory cytokine production of CD8+ T cells, including IL2, TNFα, and IFNγ. B16-OVA tumor–derived TECs induced immunosuppressive CD4+ T cells that suppressed OVA-specific CD8+ T-cell proliferation via inhibitory cytokines, including IL10 and TGFβ. Deficiency of PD-L1 in TECs, but not in hematopoietic cells, impaired suppression and apoptosis of tumor-infiltrating CD8+ T cells, resulting in inhibition of tumor development in vivo model. These data suggest that TECs might regulate the immune response of tumor Ag–specific CD8+ T cells via the PD-1/PD-L1 pathway and induce immune suppressive CD4+ T cells in an Ag-specific manner, contributing to tumor immune evasion. Implications: The findings of this study might encourage the further development of novel anticancer therapies and strategies.