RRC ID 37877
Author Kataoka K, Shiraishi Y, Takeda Y, Sakata S, Matsumoto M, Nagano S, Maeda T, Nagata Y, Kitanaka A, Mizuno S, Tanaka H, Chiba K, Ito S, Watatani Y, Kakiuchi N, Suzuki H, Yoshizato T, Yoshida K, Sanada M, Itonaga H, Imaizumi Y, Totoki Y, Munakata W, Nakamura H, Hama N, Shide K, Kubuki Y, Hidaka T, Kameda T, Masuda K, Minato N, Kashiwase K, Izutsu K, Takaori-Kondo A, Miyazaki Y, Takahashi S, Shibata T, Kawamoto H, Akatsuka Y, Shimoda K, Takeuchi K, Seya T, Miyano S, Ogawa S.
Title Aberrant PD-L1 expression through 3'-UTR disruption in multiple cancers.
Journal 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.
Volume 534(7607)
Pages 402-6
Published 2016-6-16
DOI 10.1038/nature18294
PII nature18294
PMID 27281199
MeSH 3' Untranslated Regions / genetics* Adenocarcinoma / genetics Animals Antibodies / pharmacology Antibodies / therapeutic use CRISPR-Cas Systems Cell Line, Tumor Clonal Selection, Antigen-Mediated Female Gene Expression Regulation, Neoplastic* Genetic Markers / genetics Humans Leukemia-Lymphoma, Adult T-Cell / genetics Lymphoma, Large B-Cell, Diffuse / genetics Mice Neoplasms / genetics* Neoplasms / pathology Programmed Cell Death 1 Receptor / antagonists & inhibitors Programmed Cell Death 1 Receptor / biosynthesis Programmed Cell Death 1 Receptor / genetics* RNA Stability RNA, Messenger / genetics RNA, Messenger / metabolism Stomach Neoplasms / genetics Tumor Escape / genetics* Up-Regulation*
IF 42.779
Times Cited 260
Human and Animal Cells 293T(RCB2202) PC-9(RCB4455) Jurkat(RCB0806)