Aberrant PD-L1 expression through 3′-UTR disruption in multiple cancers

Keisuke Kataoka, Yuichi Shiraishi, Yohei Takeda, Seiji Sakata, Misako Matsumoto, Seiji Nagano, Takuya Maeda, Yasunobu Nagata, Akira Kitanaka, Seiya Mizuno, Hiroko Tanaka, Kenichi Chiba, Satoshi Ito, Yosaku Watatani, Nobuyuki Kakiuchi, Hiromichi Suzuki, Tetsuichi Yoshizato, Kenichi Yoshida, Masashi Sanada, Hidehiro ItonagaYoshitaka Imaizumi, Yasushi Totoki, Wataru Munakata, Hiromi Nakamura, Natsuko Hama, Kotaro Shide, Yoko Kubuki, Tomonori Hidaka, Takuro Kameda, Kyoko Masuda, Nagahiro Minato, Koichi Kashiwase, Koji Izutsu, Akifumi Takaori-Kondo, Yasushi Miyazaki, Satoru Takahashi, Tatsuhiro Shibata, Hiroshi Kawamoto, Yoshiki Akatsuka, Kazuya Shimoda, Kengo Takeuchi, Tsukasa Seya, Satoru Miyano, Seishi Ogawa

研究成果: Article査読

288 被引用数 (Scopus)

抄録

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. 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. 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.

本文言語English
ページ(範囲)402-406
ページ数5
ジャーナルNature
534
7607
DOI
出版ステータスPublished - 23-05-2016

All Science Journal Classification (ASJC) codes

  • General

フィンガープリント 「Aberrant PD-L1 expression through 3′-UTR disruption in multiple cancers」の研究トピックを掘り下げます。これらがまとまってユニークなフィンガープリントを構成します。

引用スタイル