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

Research output: Contribution to journalArticle

213 Citations (Scopus)

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. 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.

Original languageEnglish
Pages (from-to)402-406
Number of pages5
JournalNature
Volume534
Issue number7607
DOIs
Publication statusPublished - 23-05-2016

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3' Untranslated Regions
Immune Evasion
Neoplasms
Stomach
Adenocarcinoma
Adult T Cell Leukemia Lymphoma
Lymphoma, Large B-Cell, Diffuse
Gene Amplification
B-Cell Lymphoma
Hodgkin Disease
Genetic Markers
Immunity
Cell Death
Ligands
Antibodies
Genes

All Science Journal Classification (ASJC) codes

  • General

Cite this

Kataoka, K., Shiraishi, Y., Takeda, Y., Sakata, S., Matsumoto, M., Nagano, S., ... Ogawa, S. (2016). Aberrant PD-L1 expression through 3′-UTR disruption in multiple cancers. Nature, 534(7607), 402-406. https://doi.org/10.1038/nature18294
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 ; Ogawa, Seishi. / Aberrant PD-L1 expression through 3′-UTR disruption in multiple cancers. In: Nature. 2016 ; Vol. 534, No. 7607. pp. 402-406.
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Kataoka, K, Shiraishi, Y, Takeda, Y, Sakata, S, Matsumoto, M, Nagano, S, Maeda, T, Nagata, Y, Kitanaka, A, Mizuno, S, Tanaka, H, Chiba, K, Ito, S, Watatani, Y, Kakiuchi, N, Suzuki, H, Yoshizato, T, Yoshida, K, Sanada, M, Itonaga, H, Imaizumi, Y, Totoki, Y, Munakata, W, Nakamura, H, Hama, N, Shide, K, Kubuki, Y, Hidaka, T, Kameda, T, Masuda, K, Minato, N, Kashiwase, K, Izutsu, K, Takaori-Kondo, A, Miyazaki, Y, Takahashi, S, Shibata, T, Kawamoto, H, Akatsuka, Y, Shimoda, K, Takeuchi, K, Seya, T, Miyano, S & Ogawa, S 2016, 'Aberrant PD-L1 expression through 3′-UTR disruption in multiple cancers', Nature, vol. 534, no. 7607, pp. 402-406. https://doi.org/10.1038/nature18294

Aberrant PD-L1 expression through 3′-UTR disruption in multiple cancers. / 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; Ogawa, Seishi.

In: Nature, Vol. 534, No. 7607, 23.05.2016, p. 402-406.

Research output: Contribution to journalArticle

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AU - Kataoka, Keisuke

AU - Shiraishi, Yuichi

AU - Takeda, Yohei

AU - Sakata, Seiji

AU - Matsumoto, Misako

AU - Nagano, Seiji

AU - Maeda, Takuya

AU - Nagata, Yasunobu

AU - Kitanaka, Akira

AU - Mizuno, Seiya

AU - Tanaka, Hiroko

AU - Chiba, Kenichi

AU - Ito, Satoshi

AU - Watatani, Yosaku

AU - Kakiuchi, Nobuyuki

AU - Suzuki, Hiromichi

AU - Yoshizato, Tetsuichi

AU - Yoshida, Kenichi

AU - Sanada, Masashi

AU - Itonaga, Hidehiro

AU - Imaizumi, Yoshitaka

AU - Totoki, Yasushi

AU - Munakata, Wataru

AU - Nakamura, Hiromi

AU - Hama, Natsuko

AU - Shide, Kotaro

AU - Kubuki, Yoko

AU - Hidaka, Tomonori

AU - Kameda, Takuro

AU - Masuda, Kyoko

AU - Minato, Nagahiro

AU - Kashiwase, Koichi

AU - Izutsu, Koji

AU - Takaori-Kondo, Akifumi

AU - Miyazaki, Yasushi

AU - Takahashi, Satoru

AU - Shibata, Tatsuhiro

AU - Kawamoto, Hiroshi

AU - Akatsuka, Yoshiki

AU - Shimoda, Kazuya

AU - Takeuchi, Kengo

AU - Seya, Tsukasa

AU - Miyano, Satoru

AU - Ogawa, Seishi

PY - 2016/5/23

Y1 - 2016/5/23

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Kataoka K, Shiraishi Y, Takeda Y, Sakata S, Matsumoto M, Nagano S et al. Aberrant PD-L1 expression through 3′-UTR disruption in multiple cancers. Nature. 2016 May 23;534(7607):402-406. https://doi.org/10.1038/nature18294