Aberrant PD-L1 expression through 3'-UTR disruption in multiple cancers PMID: 27281199

Target-related Cytokines

2026-09-23

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

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

Keisuke Kataoka ¹ , Yuichi Shiraishi ² , Yohei Takeda ³ , Seiji Sakata ⁴ , Misako Matsumoto ³ , Seiji Nagano ⁵ , Takuya Maeda ⁵ , Yasunobu Nagata ¹ , Akira Kitanaka ⁶ , Seiya Mizuno ⁷ , Hiroko Tanaka ² , Kenichi Chiba ² , Satoshi Ito ² , Yosaku Watatani ¹ , Nobuyuki Kakiuchi ¹ , Hiromichi Suzuki ¹ , Tetsuichi Yoshizato ¹ , Kenichi Yoshida ¹ , Masashi Sanada ⁸ , Hidehiro Itonaga ⁹ , Yoshitaka Imaizumi ¹⁰ , Yasushi Totoki ¹¹ , Wataru Munakata ¹² , Hiromi Nakamura ¹¹ , Natsuko Hama ¹¹ , Kotaro Shide ⁶ , Yoko Kubuki ⁶ , Tomonori Hidaka ⁶ , Takuro Kameda ⁶ , Kyoko Masuda ⁵ , Nagahiro Minato ¹³ , Koichi Kashiwase ¹⁴ , Koji Izutsu ¹⁵ , Akifumi Takaori-Kondo ¹⁶ , Yasushi Miyazaki ¹⁰ , Satoru Takahashi ⁷ , Tatsuhiro Shibata ¹¹ ¹⁷ , Hiroshi Kawamoto ⁵ , Yoshiki Akatsuka ¹⁸ ¹⁹ , Kazuya Shimoda ⁶ , Kengo Takeuchi ⁴ , Tsukasa Seya ³ , Satoru Miyano ² , Seishi Ogawa ¹

Affiliations

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.