Aberrant PD-L1 expression through 3'-UTR disruption in multiple cancers.
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.
Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
Keisuke
K
Kataoka
Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.
Yuichi
Y
Shiraishi
Department of Microbiology and Immunology, Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan.
Yohei
Y
Takeda
Pathology Project for Molecular Targets, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan.
Seiji
S
Sakata
Department of Microbiology and Immunology, Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan.
Misako
M
Matsumoto
Department of Immunology, Institute for Frontier Medical Science, Kyoto University, Kyoto 606-8507, Japan.
Seiji
S
Nagano
Department of Immunology, Institute for Frontier Medical Science, Kyoto University, Kyoto 606-8507, Japan.
Takuya
T
Maeda
Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
Yasunobu
Y
Nagata
Department of Gastroenterology and Hematology, Faculty of Medicine, University of Miyazaki, Miyazaki 889-1692, Japan.
Akira
A
Kitanaka
Laboratory Animal Resource Center and Faculty of Medicine, University of Tsukuba, Tsukuba 305-8575, Japan.
Seiya
S
Mizuno
Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.
Hiroko
H
Tanaka
Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.
Kenichi
K
Chiba
Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.
Satoshi
S
Ito
Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
Yosaku
Y
Watatani
Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
Nobuyuki
N
Kakiuchi
Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
Hiromichi
H
Suzuki
Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
Tetsuichi
T
Yoshizato
Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
Kenichi
K
Yoshida
Department of Advanced Diagnosis, Clinical Research Center, Nagoya Medical Center, Nagoya 460-0001, Japan.
Masashi
M
Sanada
Department of Hematology, Sasebo City General Hospital, Sasebo 857-8511, Japan.
Hidehiro
H
Itonaga
Department of Hematology, Atomic Bomb Disease and Hibakusya Medicine Unit, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki 852-8523, Japan.
Yoshitaka
Y
Imaizumi
Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo 104-0045, Japan.
Yasushi
Y
Totoki
Department of Hematology, National Cancer Center Hospital, Tokyo 104-0045, Japan.
Wataru
W
Munakata
Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo 104-0045, Japan.
Hiromi
H
Nakamura
Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo 104-0045, Japan.
Natsuko
N
Hama
Department of Gastroenterology and Hematology, Faculty of Medicine, University of Miyazaki, Miyazaki 889-1692, Japan.
Kotaro
K
Shide
Department of Gastroenterology and Hematology, Faculty of Medicine, University of Miyazaki, Miyazaki 889-1692, Japan.
Yoko
Y
Kubuki
Department of Gastroenterology and Hematology, Faculty of Medicine, University of Miyazaki, Miyazaki 889-1692, Japan.
Tomonori
T
Hidaka
Department of Gastroenterology and Hematology, Faculty of Medicine, University of Miyazaki, Miyazaki 889-1692, Japan.
Takuro
T
Kameda
Department of Immunology, Institute for Frontier Medical Science, Kyoto University, Kyoto 606-8507, Japan.
Kyoko
K
Masuda
Department of Immunology and Cell Biology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
Nagahiro
N
Minato
Department of HLA Laboratory, Japanese Red Cross Kanto-Koshinetsu Block Blood Center, Tokyo 135-8639, Japan.
Koichi
K
Kashiwase
Department of Hematology, Toranomon Hospital, Tokyo 105-8470, Japan.
Koji
K
Izutsu
Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
Akifumi
A
Takaori-Kondo
Department of Hematology, Atomic Bomb Disease and Hibakusya Medicine Unit, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki 852-8523, Japan.
Yasushi
Y
Miyazaki
Laboratory Animal Resource Center and Faculty of Medicine, University of Tsukuba, Tsukuba 305-8575, Japan.
Satoru
S
Takahashi
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.
Tatsuhiro
T
Shibata
Department of Immunology, Institute for Frontier Medical Science, Kyoto University, Kyoto 606-8507, Japan.
Hiroshi
H
Kawamoto
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.
Yoshiki
Y
Akatsuka
Department of Gastroenterology and Hematology, Faculty of Medicine, University of Miyazaki, Miyazaki 889-1692, Japan.
Kazuya
K
Shimoda
Pathology Project for Molecular Targets, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan.
Kengo
K
Takeuchi
Department of Microbiology and Immunology, Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan.
Tsukasa
T
Seya
Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.
Satoru
S
Miyano
Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
Seishi
S
Ogawa
D020413:3' Untranslated Regions / Q000235:genetics*; D000230:Adenocarcinoma / Q000235:genetics; D000818:Animals; D000906:Antibodies / Q000494:pharmacology / Q000627:therapeutic use; D064113:CRISPR-Cas Systems; D045744:Cell Line, Tumor; D060966:Clonal Selection, Antigen-Mediated; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005819:Genetic Markers / Q000235:genetics; D006801:Humans; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000235:genetics; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics; D051379:Mice; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*; D020871:RNA Stability; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013274:Stomach Neoplasms / Q000235:genetics; D019139:Tumor Escape / Q000235:genetics*; D015854:Up-Regulation
D020413:3' Untranslated Regions; D000906:Antibodies; D005819:Genetic Markers; C105992:PDCD1 protein, human; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D012333:RNA, Messenger