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Nature. 2016 Jun 16;534(7607):402-6. doi: 10.1038/nature18294. Epub 2016 May 23.

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

Author information

1
Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
2
Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.
3
Department of Microbiology and Immunology, Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan.
4
Pathology Project for Molecular Targets, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan.
5
Department of Immunology, Institute for Frontier Medical Science, Kyoto University, Kyoto 606-8507, Japan.
6
Department of Gastroenterology and Hematology, Faculty of Medicine, University of Miyazaki, Miyazaki 889-1692, Japan.
7
Laboratory Animal Resource Center and Faculty of Medicine, University of Tsukuba, Tsukuba 305-8575, Japan.
8
Department of Advanced Diagnosis, Clinical Research Center, Nagoya Medical Center, Nagoya 460-0001, Japan.
9
Department of Hematology, Sasebo City General Hospital, Sasebo 857-8511, Japan.
10
Department of Hematology, Atomic Bomb Disease and Hibakusya Medicine Unit, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki 852-8523, Japan.
11
Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo 104-0045, Japan.
12
Department of Hematology, National Cancer Center Hospital, Tokyo 104-0045, Japan.
13
Department of Immunology and Cell Biology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
14
Department of HLA Laboratory, Japanese Red Cross Kanto-Koshinetsu Block Blood Center, Tokyo 135-8639, Japan.
15
Department of Hematology, Toranomon Hospital, Tokyo 105-8470, Japan.
16
Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
17
Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.
18
Department of Hematology, Fujita Health University School of Medicine, Toyoake 470-1192, Japan.
19
Division of Immunology, Aichi Cancer Center Research Institute, Nagoya 464-8681, Japan.

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.

PMID:
27281199
DOI:
10.1038/nature18294
[Indexed for MEDLINE]

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