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 development1,2,3,4,5,6. 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 adenocarcinoma6,7,8,9,10. 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.
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Sequencing data have been deposited in the European Genome-phenome Archive (EGA) under accession EGAS00001001296 (https://www.ebi.ac.uk/ega/studies/EGAS00001001296).
This work was supported by Grant-in-Aid from the Japan Agency for Medical Research and Development (Practical Research for Innovative Cancer Control (15Ack0106014h0002) and Medical Research and Development Programs Focused on Technology Transfer (15im0210102h0001)), Grant-in-Aid for Scientific Research (KAKENHI 22134006, 15H05909, 25250020), and National Cancer Center Research and Development Funds (26-A-6). We thank M. Sago, M. Nakamura and S. Baba for technical assistance, and R. Velaga for English editing. The supercomputing resources were provided by the Human Genome Center, the Institute of Medical Science, the University of Tokyo. This research also used computational resources of the K computer provided by the RIKEN Advanced Institute for Computational Science through the HPCI System Research project (hp140230, hp160219, and hp150232). The results shown here are partly based on data generated by the TCGA Research Network (http://cancergenome.nih.gov/).
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About this article
Nature Communications (2018)