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PMID: 27281199 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

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

Nature ·Vol. 534 ·No. 7607 ·2016-00-16 ·Pages 402-6

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

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.

MeSH Terms
3' Untranslated Regions/genetics Adenocarcinoma/genetics Animals Antibodies/pharmacology,therapeutic use CRISPR-Cas Systems Cell Line, Tumor Clonal Selection, Antigen-Mediated Female Gene Expression Regulation, Neoplastic Genetic Markers/genetics Humans Leukemia-Lymphoma, Adult T-Cell/genetics Lymphoma, Large B-Cell, Diffuse/genetics Mice Neoplasms/genetics,pathology Programmed Cell Death 1 Receptor/antagonists & inhibitors,biosynthesis,genetics RNA Stability RNA, Messenger/genetics,metabolism Stomach Neoplasms/genetics Tumor Escape/genetics Up-Regulation
Chemicals
3' Untranslated Regions Antibodies Genetic Markers PDCD1 protein, human Pdcd1 protein, mouse Programmed Cell Death 1 Receptor RNA, Messenger
Authors & Affiliations
44 authors, click to expand affiliations / ORCID
Kataoka Keisuke
Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
Shiraishi Yuichi
Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.
Takeda Yohei
Department of Microbiology and Immunology, Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan.
Sakata Seiji
Pathology Project for Molecular Targets, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan.
Matsumoto Misako
Department of Microbiology and Immunology, Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan.
Nagano Seiji
Department of Immunology, Institute for Frontier Medical Science, Kyoto University, Kyoto 606-8507, Japan.
Maeda Takuya
Department of Immunology, Institute for Frontier Medical Science, Kyoto University, Kyoto 606-8507, Japan.
Nagata Yasunobu
Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
Kitanaka Akira
Department of Gastroenterology and Hematology, Faculty of Medicine, University of Miyazaki, Miyazaki 889-1692, Japan.
Mizuno Seiya
Laboratory Animal Resource Center and Faculty of Medicine, University of Tsukuba, Tsukuba 305-8575, Japan.
Tanaka Hiroko
Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.
Chiba Kenichi
Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.
Ito Satoshi
Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.
Watatani Yosaku
Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
Kakiuchi Nobuyuki
Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
Suzuki Hiromichi
Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
Yoshizato Tetsuichi
Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
Yoshida Kenichi
Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
Sanada Masashi
Department of Advanced Diagnosis, Clinical Research Center, Nagoya Medical Center, Nagoya 460-0001, Japan.
Itonaga Hidehiro
Department of Hematology, Sasebo City General Hospital, Sasebo 857-8511, Japan.
Imaizumi Yoshitaka
Department of Hematology, Atomic Bomb Disease and Hibakusya Medicine Unit, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki 852-8523, Japan.
Totoki Yasushi
Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo 104-0045, Japan.
Munakata Wataru
Department of Hematology, National Cancer Center Hospital, Tokyo 104-0045, Japan.
Nakamura Hiromi
Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo 104-0045, Japan.
Hama Natsuko
Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo 104-0045, Japan.
Shide Kotaro
Department of Gastroenterology and Hematology, Faculty of Medicine, University of Miyazaki, Miyazaki 889-1692, Japan.
Kubuki Yoko
Department of Gastroenterology and Hematology, Faculty of Medicine, University of Miyazaki, Miyazaki 889-1692, Japan.
Hidaka Tomonori
Department of Gastroenterology and Hematology, Faculty of Medicine, University of Miyazaki, Miyazaki 889-1692, Japan.
Kameda Takuro
Department of Gastroenterology and Hematology, Faculty of Medicine, University of Miyazaki, Miyazaki 889-1692, Japan.
Masuda Kyoko
Department of Immunology, Institute for Frontier Medical Science, Kyoto University, Kyoto 606-8507, Japan.
Minato Nagahiro
Department of Immunology and Cell Biology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
Kashiwase Koichi
Department of HLA Laboratory, Japanese Red Cross Kanto-Koshinetsu Block Blood Center, Tokyo 135-8639, Japan.
Izutsu Koji
Department of Hematology, Toranomon Hospital, Tokyo 105-8470, Japan.
Takaori-Kondo Akifumi
Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
Miyazaki Yasushi
Department of Hematology, Atomic Bomb Disease and Hibakusya Medicine Unit, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki 852-8523, Japan.
Takahashi Satoru
Laboratory Animal Resource Center and Faculty of Medicine, University of Tsukuba, Tsukuba 305-8575, Japan.
Shibata Tatsuhiro
Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo 104-0045, Japan. | Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.
Kawamoto Hiroshi
Department of Immunology, Institute for Frontier Medical Science, Kyoto University, Kyoto 606-8507, Japan.
Akatsuka Yoshiki
Department of Hematology, Fujita Health University School of Medicine, Toyoake 470-1192, Japan. | Division of Immunology, Aichi Cancer Center Research Institute, Nagoya 464-8681, Japan.
Shimoda Kazuya
Department of Gastroenterology and Hematology, Faculty of Medicine, University of Miyazaki, Miyazaki 889-1692, Japan.
Takeuchi Kengo
Pathology Project for Molecular Targets, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan.
Seya Tsukasa
Department of Microbiology and Immunology, Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan.
Miyano Satoru
Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.
Ogawa Seishi
Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
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Article Info
Journal
Nature
Abbr.
Nature
ISSN
1476-4687
DOI
10.1038/nature18294
Published
2016-00-16
Epub
2016-00-23
Pages
402-6
Language
English
Region
England
NLM ID
0410462
Subset
IM
Corrections
CommentIn
PMID: 27265363
CommentIn
PMID: 27273043
External Links
PubMed source DOI: 10.1038/nature18294 View journal details
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