Aberrant PD-L1 expression through 3′-UTR disruption in multiple cancers
Aberrant PD-L1 expression through 3′-UTR disruption in multiple cancers
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DOI：
10.1038/nature18294
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发表时间：
2016-06-16
期刊：
影响因子：
64.8
通讯作者：
Ogawa, Seishi
中科院分区：
文献类型：
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作者：
Kataoka, Keisuke;Shiraishi, Yuichi;Ogawa, Seishi
使用抗程序性细胞死亡 1 (PD-1；也称为 PDCD1) 及其配体 (PD-L1；也称为 CD274) 的抗体成功治疗了许多晚期癌症患者，这凸显了 PD-1/PD-L1 介导的免疫逃逸在癌症发展中的至关重要性 (1-6)。然而，除了霍奇金和其他 B 细胞淋巴瘤以及胃腺癌中报道的通过基因扩增和通过易位利用异位启动子而导致 PD-L1 表达升高之外，免疫逃逸的遗传基础尚未完全阐明(6-10)。在这里，我们展示了由通常破坏 PD-L1 基因 3' 区域的结构变异 (SV) 引起的免疫逃逸的独特遗传机制。这些 SV 广泛影响多种常见的人类癌症类型，包括成人 T 细胞白血病/淋巴瘤 (27%)、弥漫性大 B 细胞淋巴瘤 (8%) 和胃腺癌 (2%)，它们总是导致异常 PD-L1 转录物显着升高，而通过截断 3'-非翻译区 (UTR) 可稳定这些转录物。小鼠中 Pd-l1 3'-UTR 的破坏使得体内 Pd-l1 表达升高的 EG7-OVA 肿瘤细胞能够进行免疫逃避，Pd-1/Pd-l1 阻断可有效抑制这种表达，支持相关 SV 通过免疫逃避在克隆选择中的作用。我们的研究结果不仅揭示了 PD-L1 表达的新调控机制，而且还表明 PD-L1 3'-UTR 破坏可以作为遗传标记来识别通过 PD-L1 过表达主动逃避抗肿瘤免疫的癌症。
Successful treatment of many patients with advanced cancer using antibodies against programmed cell death 1 (PD-1; also known as PDCD1) and its ligand (PD-L1; also known as CD274) has highlighted the critical importance of PD-1/PD-L1-mediated immune escape in cancer development(1-6). However, the genetic basis for the immune escape has not been fully elucidated, with the exception of elevated PD-L1 expression by gene amplification and utilization of an ectopic promoter by translocation, as reported in Hodgkin and other B-cell lymphomas, as well as stomach adenocarcinoma(6-10). Here we show a unique genetic mechanism of immune escape caused by structural variations (SVs) commonly disrupting the 3' region of the PD-L1 gene. Widely affecting multiple common human cancer types, including adult T-cell leukaemia/lymphoma (27%), diffuse large B-cell lymphoma (8%), and stomach adenocarcinoma (2%), these SVs invariably lead to a marked elevation of aberrant PD-L1 transcripts that are stabilized by truncation of the 3'-untranslated region (UTR). Disruption of the Pd-l1 3'-UTR in mice enables immune evasion of EG7-OVA tumour cells with elevated Pd-l1 expression in vivo, which is effectively inhibited by Pd-1/Pd-l1 blockade, supporting the role of relevant SVs in clonal selection through immune evasion. Our findings not only unmask a novel regulatory mechanism of PD-L1 expression, but also suggest that PD-L1 3'-UTR disruption could serve as a genetic marker to identify cancers that actively evade anti-tumour immunity through PD-L1 overexpression.