抑制外泌体 PD-L1 诱导全身性抗肿瘤免疫和记忆。
Suppression of Exosomal PD-L1 Induces Systemic Anti-tumor Immunity and Memory.
机构信息
Department of Urology, University of California, San Francisco, San Francisco, CA 94143, USA; Eli and Edith Broad Institute for Regeneration Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
出版信息
Cell. 2019 Apr 4;177(2):414-427.e13. doi: 10.1016/j.cell.2019.02.016.
PD-L1 on the surface of tumor cells binds its receptor PD-1 on effector T cells, thereby suppressing their activity. Antibody blockade of PD-L1 can activate an anti-tumor immune response leading to durable remissions in a subset of cancer patients. Here, we describe an alternative mechanism of PD-L1 activity involving its secretion in tumor-derived exosomes. Removal of exosomal PD-L1 inhibits tumor growth, even in models resistant to anti-PD-L1 antibodies. Exosomal PD-L1 from the tumor suppresses T cell activation in the draining lymph node. Systemically introduced exosomal PD-L1 rescues growth of tumors unable to secrete their own. Exposure to exosomal PD-L1-deficient tumor cells suppresses growth of wild-type tumor cells injected at a distant site, simultaneously or months later. Anti-PD-L1 antibodies work additively, not redundantly, with exosomal PD-L1 blockade to suppress tumor growth. Together, these findings show that exosomal PD-L1 represents an unexplored therapeutic target, which could overcome resistance to current antibody approaches.
肿瘤细胞表面的 PD-L1 与其效应 T 细胞上的受体 PD-1 结合，从而抑制其活性。抗体阻断 PD-L1 可以激活抗肿瘤免疫反应，导致一部分癌症患者获得持久缓解。在这里，我们描述了 PD-L1 活性的另一种机制，涉及肿瘤衍生的外泌体中 PD-L1 的分泌。去除外泌体 PD-L1 可抑制肿瘤生长，即使在对抗 PD-L1 抗体耐药的模型中也是如此。肿瘤来源的外泌体 PD-L1 抑制引流淋巴结中 T 细胞的激活。系统引入外泌体 PD-L1 可挽救不能分泌自身外泌体的肿瘤的生长。暴露于缺乏外泌体 PD-L1 的肿瘤细胞可抑制同时或数月后注射的野生型肿瘤细胞的生长。抗 PD-L1 抗体与外泌体 PD-L1 阻断协同作用，而非冗余作用，以抑制肿瘤生长。总之，这些发现表明外泌体 PD-L1 代表了一个未被探索的治疗靶点，它可以克服对当前抗体方法的耐药性。
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