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

1. Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
Authors
Kataoka K¹
Nagata Y¹
Watatani Y¹
Kakiuchi N¹
Suzuki H¹
Yoshizato T¹
Yoshida K¹
Ogawa S¹
(8 authors)
2. Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.
Authors
Shiraishi Y²
Tanaka H²
Chiba K²
Ito S²
Miyano S²
(5 authors)
3. Department of Microbiology and Immunology, Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan.
Authors
Takeda Y³
Matsumoto M³
Seya T³
(3 authors)
4. Pathology Project for Molecular Targets, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan.
Authors
Sakata S⁴
Takeuchi K⁴
(2 authors)
5. Department of Immunology, Institute for Frontier Medical Science, Kyoto University, Kyoto 606-8507, Japan.
Authors
Nagano S⁵
Maeda T⁵
Masuda K⁵
Kawamoto H⁵
(4 authors)

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Nature, 23 May 2016, 534(7607):402-406
https://doi.org/10.1038/nature18294 PMID: 27281199

A comment on this article appears in "Cancer genetics: Evading antitumour immunity." Nat Rev Genet. 2016 Jul;17(7):374. A comment on this article appears in "Immunotherapy: Study deciphers enigmatic mechanism of PD-L1 overexpression." Nat Rev Clin Oncol. 2016 Jul;13(7):395.

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.