Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 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

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

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

Keisuke Kataoka et al. Nature. .

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.

PubMed Disclaimer

Comment in

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Nat Rev Genet. 2012 Mar 06;13(4):246-59 - PubMed
    1. Blood. 2010 Oct 28;116(17):3268-77 - PubMed
    1. Cell. 2013 Mar 28;153(1):17-37 - PubMed
    1. Genome Res. 2000 Jul;10(7):1001-10 - PubMed
    1. Cancer Cell. 2015 Apr 13;27(4):450-61 - PubMed

Publication types

MeSH terms