1. Aberrant PD-L1 expression through 3'-UTR disruption in multiple cancers
- Author
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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, Masuda, Kyoko, Minato, Nagahiro, Kashiwase, Koichi, Izutsu, Koji, Takaori-Kondo, Akifumi, Miyazaki, Yasushi, Takahashi, Satoru, Shibata, Tatsuhiro, Kawamoto, Hiroshi, Akatsuka, Yoshiki, Shimoda, Kazuya, Takeuchi, Kengo, Seya, Tsukasa, Miyano, Satoru, and Ogawa, Seishi
- Subjects
Gene expression -- Health aspects ,Ligands (Biochemistry) -- Properties ,Genetic variation -- Health aspects ,Cancer -- Care and treatment ,Molecular targeted therapy ,Environmental issues ,Science and technology ,Zoology and wildlife conservation - Abstract
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., Structural variations, including translocations, inversions, tandem duplications, and deletions, are widely observed across cancer genomes (11,12). Of particular interest are those involving non-coding sequences recently reported for activation of several [...]
- Published
- 2016