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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.
Afiliação
  • Kataoka K; Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
  • Shiraishi Y; Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.
  • Takeda Y; Department of Microbiology and Immunology, Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan.
  • Sakata S; Pathology Project for Molecular Targets, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan.
  • Matsumoto M; Department of Microbiology and Immunology, Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan.
  • Nagano S; Department of Immunology, Institute for Frontier Medical Science, Kyoto University, Kyoto 606-8507, Japan.
  • Maeda T; Department of Immunology, Institute for Frontier Medical Science, Kyoto University, Kyoto 606-8507, Japan.
  • Nagata Y; Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
  • Kitanaka A; Department of Gastroenterology and Hematology, Faculty of Medicine, University of Miyazaki, Miyazaki 889-1692, Japan.
  • Mizuno S; Laboratory Animal Resource Center and Faculty of Medicine, University of Tsukuba, Tsukuba 305-8575, Japan.
  • Tanaka H; Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.
  • Chiba K; Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.
  • Ito S; Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.
  • Watatani Y; Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
  • Kakiuchi N; Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
  • Suzuki H; Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
  • Yoshizato T; Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
  • Yoshida K; Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
  • Sanada M; Department of Advanced Diagnosis, Clinical Research Center, Nagoya Medical Center, Nagoya 460-0001, Japan.
  • Itonaga H; Department of Hematology, Sasebo City General Hospital, Sasebo 857-8511, Japan.
  • Imaizumi Y; Department of Hematology, Atomic Bomb Disease and Hibakusya Medicine Unit, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki 852-8523, Japan.
  • Totoki Y; Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo 104-0045, Japan.
  • Munakata W; Department of Hematology, National Cancer Center Hospital, Tokyo 104-0045, Japan.
  • Nakamura H; Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo 104-0045, Japan.
  • Hama N; Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo 104-0045, Japan.
  • Shide K; Department of Gastroenterology and Hematology, Faculty of Medicine, University of Miyazaki, Miyazaki 889-1692, Japan.
  • Kubuki Y; Department of Gastroenterology and Hematology, Faculty of Medicine, University of Miyazaki, Miyazaki 889-1692, Japan.
  • Hidaka T; Department of Gastroenterology and Hematology, Faculty of Medicine, University of Miyazaki, Miyazaki 889-1692, Japan.
  • Kameda T; Department of Gastroenterology and Hematology, Faculty of Medicine, University of Miyazaki, Miyazaki 889-1692, Japan.
  • Masuda K; Department of Immunology, Institute for Frontier Medical Science, Kyoto University, Kyoto 606-8507, Japan.
  • Minato N; Department of Immunology and Cell Biology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
  • Kashiwase K; Department of HLA Laboratory, Japanese Red Cross Kanto-Koshinetsu Block Blood Center, Tokyo 135-8639, Japan.
  • Izutsu K; Department of Hematology, Toranomon Hospital, Tokyo 105-8470, Japan.
  • Takaori-Kondo A; Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
  • Miyazaki Y; Department of Hematology, Atomic Bomb Disease and Hibakusya Medicine Unit, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki 852-8523, Japan.
  • Takahashi S; Laboratory Animal Resource Center and Faculty of Medicine, University of Tsukuba, Tsukuba 305-8575, Japan.
  • Shibata T; Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo 104-0045, Japan.
  • Kawamoto H; Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.
  • Akatsuka Y; Department of Immunology, Institute for Frontier Medical Science, Kyoto University, Kyoto 606-8507, Japan.
  • Shimoda K; Department of Hematology, Fujita Health University School of Medicine, Toyoake 470-1192, Japan.
  • Takeuchi K; Division of Immunology, Aichi Cancer Center Research Institute, Nagoya 464-8681, Japan.
  • Seya T; Department of Gastroenterology and Hematology, Faculty of Medicine, University of Miyazaki, Miyazaki 889-1692, Japan.
  • Miyano S; Pathology Project for Molecular Targets, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan.
  • Ogawa S; Department of Microbiology and Immunology, Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan.
Nature ; 534(7607): 402-6, 2016 06 16.
Article em En | MEDLINE | ID: mdl-27281199
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.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Regulação Neoplásica da Expressão Gênica / Regulação para Cima / Evasão Tumoral / Regiões 3' não Traduzidas / Receptor de Morte Celular Programada 1 / Neoplasias Tipo de estudo: Prognostic_studies Limite: Animals / Female / Humans Idioma: En Revista: Nature Ano de publicação: 2016 Tipo de documento: Article País de afiliação: Japão

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Regulação Neoplásica da Expressão Gênica / Regulação para Cima / Evasão Tumoral / Regiões 3' não Traduzidas / Receptor de Morte Celular Programada 1 / Neoplasias Tipo de estudo: Prognostic_studies Limite: Animals / Female / Humans Idioma: En Revista: Nature Ano de publicação: 2016 Tipo de documento: Article País de afiliação: Japão