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 development1,2,3,4,5,6. 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 adenocarcinoma6,7,8,9,10. 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.

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Data deposits

Sequencing data have been deposited in the European Genome-phenome Archive (EGA) under accession EGAS00001001296 (https://www.ebi.ac.uk/ega/studies/EGAS00001001296).

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Acknowledgements

This work was supported by Grant-in-Aid from the Japan Agency for Medical Research and Development (Practical Research for Innovative Cancer Control (15Ack0106014h0002) and Medical Research and Development Programs Focused on Technology Transfer (15im0210102h0001)), Grant-in-Aid for Scientific Research (KAKENHI 22134006, 15H05909, 25250020), and National Cancer Center Research and Development Funds (26-A-6). We thank M. Sago, M. Nakamura and S. Baba for technical assistance, and R. Velaga for English editing. The supercomputing resources were provided by the Human Genome Center, the Institute of Medical Science, the University of Tokyo. This research also used computational resources of the K computer provided by the RIKEN Advanced Institute for Computational Science through the HPCI System Research project (hp140230, hp160219, and hp150232). The results shown here are partly based on data generated by the TCGA Research Network (http://cancergenome.nih.gov/).

Author information

Author notes

    • Keisuke Kataoka
    • , Yuichi Shiraishi
    •  & Yohei Takeda

    These authors contributed equally to this work.

Affiliations

  1. Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan

    • Keisuke Kataoka
    • , Yasunobu Nagata
    • , Yosaku Watatani
    • , Nobuyuki Kakiuchi
    • , Hiromichi Suzuki
    • , Tetsuichi Yoshizato
    • , Kenichi Yoshida
    •  & Seishi Ogawa
  2. Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan

    • Yuichi Shiraishi
    • , Hiroko Tanaka
    • , Kenichi Chiba
    • , Satoshi Ito
    •  & Satoru Miyano
  3. Department of Microbiology and Immunology, Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan

    • Yohei Takeda
    • , Misako Matsumoto
    •  & Tsukasa Seya
  4. Pathology Project for Molecular Targets, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan

    • Seiji Sakata
    •  & Kengo Takeuchi
  5. Department of Immunology, Institute for Frontier Medical Science, Kyoto University, Kyoto 606-8507, Japan

    • Seiji Nagano
    • , Takuya Maeda
    • , Kyoko Masuda
    •  & Hiroshi Kawamoto
  6. Department of Gastroenterology and Hematology, Faculty of Medicine, University of Miyazaki, Miyazaki 889-1692, Japan

    • Akira Kitanaka
    • , Kotaro Shide
    • , Yoko Kubuki
    • , Tomonori Hidaka
    • , Takuro Kameda
    •  & Kazuya Shimoda
  7. Laboratory Animal Resource Center and Faculty of Medicine, University of Tsukuba, Tsukuba 305-8575, Japan

    • Seiya Mizuno
    •  & Satoru Takahashi
  8. Department of Advanced Diagnosis, Clinical Research Center, Nagoya Medical Center, Nagoya 460-0001, Japan

    • Masashi Sanada
  9. Department of Hematology, Sasebo City General Hospital, Sasebo 857-8511, Japan

    • Hidehiro Itonaga
  10. Department of Hematology, Atomic Bomb Disease and Hibakusya Medicine Unit, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki 852-8523, Japan

    • Yoshitaka Imaizumi
    •  & Yasushi Miyazaki
  11. Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo 104-0045, Japan

    • Yasushi Totoki
    • , Hiromi Nakamura
    • , Natsuko Hama
    •  & Tatsuhiro Shibata
  12. Department of Hematology, National Cancer Center Hospital, Tokyo 104-0045, Japan

    • Wataru Munakata
  13. Department of Immunology and Cell Biology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan

    • Nagahiro Minato
  14. Department of HLA Laboratory, Japanese Red Cross Kanto-Koshinetsu Block Blood Center, Tokyo 135-8639, Japan

    • Koichi Kashiwase
  15. Department of Hematology, Toranomon Hospital, Tokyo 105-8470, Japan

    • Koji Izutsu
  16. Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan

    • Akifumi Takaori-Kondo
  17. Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan

    • Tatsuhiro Shibata
  18. Department of Hematology, Fujita Health University School of Medicine, Toyoake 470-1192, Japan

    • Yoshiki Akatsuka
  19. Division of Immunology, Aichi Cancer Center Research Institute, Nagoya 464-8681, Japan

    • Yoshiki Akatsuka

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Contributions

K.Kataoka, Y.S., H.T., K.C., S.I., and S.Miyano performed sequencing data analyses. H.S., T.Y., Y.Totoki, H.N., N.H. and T.Shibata assisted sequencing data analyses. K.Kataoka, Y.N., Y.W., N.K., K.Y., M.S. and K.Kashiwase performed sequencing experiments. K.Kataoka, S.N., T.M., K.M., N.M., H.K., and Y.A. performed functional assays. S.Mizuno. and S.T. designed sgRNAs. Y.Takeda, M.M., and T.Seya performed in vivo experiments. S.S. and K.T. performed IHC assay. A.K., H.I., Y.I., W.M., K.Shide, Y.K., T.H., T.K., K.I., A.T.-K., Y.M., and K.Shimoda collected specimens. K.Kataoka, Y.S., and S.O. generated figures and tables and wrote the manuscript. S.O. led the entire project. All authors participated in discussions and interpretation of the data and results.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Seishi Ogawa.

Reviewer information Nature thanks J. Cools, M. Meyerson and A. Ribas for their contribution to the peer review of this work

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DOI

https://doi.org/10.1038/nature18294

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