Cell //外泌体PD-L1缺陷诱导系统性抗肿瘤免疫和记忆

Suppression of ExosomalPD-L1 Induces Systemic Anti-tumor Immunity and Memory

Mauro Poggio, TianyiHu, Chien-Chun Pai, Brandon Chu, Cassandra D. Belair, Anthony Chang, ElizabethMontabana, Ursula E. Lang, Qi Fu, Lawrence Fong, and Robert Blelloch

Cell (IF36.216) Pub date: 2019-4-4

Doi: 10.1016/j.cell.2019.02.016

Abstract：

PD-L1 on the surface of tumor cells binds its receptor PD-1on effector T cells, thereby suppressing their activity. Antibody blockade ofPD-L1 can activate an anti-tumor immune response leading to durable remissionsin a subset of cancer patients. Here, we describe an alternative mechanism ofPD-L1 activity involving its secretion in tumor-derived exosomes. Removal ofexosomal PD-L1 inhibits tumor growth, even in models resistant to anti-PD-L1antibodies. Exosomal PD-L1 from the tumor suppresses T cell activation in thedraining lymph node. Systemically introduced exosomal PD-L1 rescues growth oftumors unable to secrete their own. Exposure to exosomal PD-L1-deficient tumorcells suppresses growth of wild-type tumor cells injected at a distant site,simultaneously ormonths later. Anti-PD-L1 antibodies work additively, notredundantly, with exosomal PD-L1 blockade to suppress tumor growth. Together,these findings show that exosomal PD-L1 represents an unexplored therapeutictarget, which could overcome resistance to current antibody approaches.  

推荐理由：

1.该文章详述了外泌体PD-L1如何系统性的抑制抗肿瘤效果，也证明基因阻断远端失活机理可提高引流淋巴结中T细胞活性，并引起系统性抗肿瘤免疫和记忆。本文作者提出了4个观点：阻断肿瘤细胞分泌带有PD-L1的外泌体能通过提高抗肿瘤免疫反应而延长生存期；外泌体PD-L1能够抑制引流淋巴结中T细胞的活性；外泌体缺陷肿瘤细胞能够引起系统性抗肿瘤免疫和记忆；外泌体的PD-L1对PD-L1抑制剂具有抵抗作用。

2.暂时性的抑制外泌体PD-L1的释放，也能导致长期的、全身的肿瘤生长抑制。这可能成为一种新的免疫治疗方法，即通过对患者肿瘤细胞的编辑和回输来激活患者的免疫系统，进而消灭免疫抵抗的癌细胞。或许，在不远的将来，抑制外泌体PD-L1的释放或接种由Blelloch团队设计的“肿瘤细胞疫苗”，将为一些现有治疗手段无效的患者带来希望。

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