Aberrant PD-L1 expression through 3 %26apos;-UTR disruption in multiple cancers

作者：Kataoka Keisuke; Shiraishi Yuichi; Takeda Yohei; Sakata Seiji; Matsumoto Misako; Nagano Seiji; Maeda Takuya; Nagata Yasunobu; Kitanaka Akira; Mizuno Seiya; Tanaka Hiroko; Chiba Kenichi; Ito Satoshi; Watatani Yosaku; Kakiuchi Nobuyuki; Suzuki Hiromichi; Yoshizato Tetsuichi; Yoshida Kenichi; Sanada Masashi; Itonaga Hidehiro; Imaizumi Yoshitaka; Totoki Yasushi; Munakata Wataru; Nakamura Hiromi; Hama Natsuko; Shide Kotaro; Kubuki Yoko; Hidaka Tomonori; Kameda Takuro

来源：Nature, 2016, 534(7607): 402-+.

DOI：10.1038/nature18294

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.

• 出版日期2016-6-16
• 单位河北医科大学