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

被引：584

作者：

Kataoka, Keisuke ^{[1
]}

Shiraishi, Yuichi ^{[2
]}

Takeda, Yohei ^{[3
]}

Sakata, Seiji ^{[4
]}

Matsumoto, Misako ^{[3
]}

Nagano, Seiji ^{[5
]}

Maeda, Takuya ^{[5
]}

Nagata, Yasunobu ^{[1
]}

Kitanaka, Akira ^{[6
]}

Mizuno, Seiya ^{[7
,8
]}

Tanaka, Hiroko ^{[2
]}

Chiba, Kenichi ^{[2
]}

Ito, Satoshi ^{[2
]}

Watatani, Yosaku ^{[1
]}

Kakiuchi, Nobuyuki ^{[1
]}

Suzuki, Hiromichi ^{[1
]}

Yoshizato, Tetsuichi ^{[1
]}

Yoshida, Kenichi ^{[1
]}

Sanada, Masashi ^{[9
]}

Itonaga, Hidehiro ^{[10
]}

Imaizumi, Yoshitaka ^{[11
]}

Totoki, Yasushi ^{[12
]}

Munakata, Wataru ^{[13
]}

Nakamura, Hiromi ^{[12
]}

Hama, Natsuko ^{[12
]}

Shide, Kotaro ^{[6
]}

Kubuki, Yoko ^{[6
]}

Hidaka, Tomonori ^{[6
]}

Kameda, Takuro ^{[6
]}

Masuda, Kyoko ^{[5
]}

Minato, Nagahiro ^{[14
]}

Kashiwase, Koichi ^{[15
]}

Izutsu, Koji ^{[16
]}

Takaori-Kondo, Akifumi ^{[17
]}

Miyazaki, Yasushi ^{[11
]}

Takahashi, Satoru ^{[7
,8
]}

Shibata, Tatsuhiro ^{[12
,18
]}

Kawamoto, Hiroshi ^{[5
]}

Akatsuka, Yoshiki ^{[19
,20
]}

Shimoda, Kazuya ^{[6
]}

Takeuchi, Kengo ^{[4
]}

Seya, Tsukasa ^{[3
]}

Miyano, Satoru ^{[2
]}

Ogawa, Seishi ^{[1
]}

机构：

[1] Kyoto Univ, Grad Sch Med, Dept Pathol & Tumor Biol, Kyoto 6068501, Japan

[2] Univ Tokyo, Inst Med Sci, Ctr Human Genome, Lab DNA Informat Anal, Tokyo 1088639, Japan

[3] Hokkaido Univ, Grad Sch Med, Dept Microbiol & Immunol, Sapporo, Hokkaido 0608638, Japan

[4] Japanese Fdn Canc Res, Inst Canc, Pathol Project Mol Targets, Tokyo 1358550, Japan

[5] Kyoto Univ, Inst Frontier Med Sci, Dept Immunol, Kyoto 6068507, Japan

[6] Miyazaki Univ, Dept Gastroenterol & Hematol, Fac Med, Miyazaki 8891692, Japan

[7] Univ Tsukuba, Lab Anim Resource Ctr, Tsukuba, Ibaraki 3058575, Japan

[8] Univ Tsukuba, Fac Med, Tsukuba, Ibaraki 3058575, Japan

[9] Nagoya Med Ctr, Dept Adv Diag, Clin Res Ctr, Nagoya, Aichi 4600001, Japan

[10] Sasebo City Gen Hosp, Dept Hematol, Sasebo 8578511, Japan

[11] Nagasaki Univ, Atom Bomb Dis Inst, Atom Bomb Dis & Hibakusya Med Unit, Dept Hematol, Nagasaki 8528523, Japan

[12] Natl Canc Ctr, Div Canc Genom, Tokyo 1040045, Japan

[13] Natl Canc Ctr, Dept Hematol, Tokyo 1040045, Japan

[14] Kyoto Univ, Grad Sch Med, Dept Immunol & Cell Biol, Kyoto 6068501, Japan

[15] Japanese Red Cross Kanto Koshinetsu Block Blood C, Dept HLA Lab, Tokyo 1358639, Japan

[16] Toranomon Gen Hosp, Dept Hematol, Tokyo 1058470, Japan

[17] Kyoto Univ, Grad Sch Med, Dept Hematol & Oncol, Kyoto 6068501, Japan

[18] Univ Tokyo, Inst Med Sci, Ctr Human Genome, Lab Mol Med, Tokyo 1088639, Japan

[19] Fujita Hlth Univ, Sch Med, Sch Med, Toyoake, Aichi 4701192, Japan

[20] Aichi Canc Ctr, Div Immunol, Res Inst, Nagoya, Aichi 4648681, Japan

来源：

NATURE | 2016年 / 534卷 / 7607期

关键词：

GENOMIC REARRANGEMENTS; POLYMORPHISM; GENE; ACTIVATION; ONCOGENES; BLOCKADE; ANTIBODY; SAFETY; CELLS; RISK;

D O I：

10.1038/nature18294

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];

摘要：

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.

引用

页码：402 / +

页数：17

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