Journal article
Pan-cancer Landscape of Programmed Death Ligand-1 and Programmed Death Ligand-2 Structural Variations
JCO precision oncology, Vol.7(7), p.e2200300
01/2023
DOI: 10.1200/PO.22.00300
PMCID: PMC9928630
PMID: 36623238
Abstract
PURPOSE Programmed cell death protein-1 (PD-1) receptor and ligand interactions are the target of immunotherapies for more than 20 cancer types. Biomarkers that predict response to immunotherapy are microsatellite instability, tumor mutational burden, and programmed death ligand-1 (PD-L1) immunohistochemistry. Structural variations (SVs) in PD-L1 ( CD274) and PD-L2 ( PDCD1LG2) have been observed in cancer, but the comprehensive landscape is unknown. Here, we describe the genomic landscape of PD-L1 and PD-L2 SVs, their potential impact on the tumor microenvironment, and evidence that patients with these alterations can benefit from immunotherapy. METHODS We analyzed sequencing data from cancer cases with PD-L1 and PD-L2 SVs across 22 publications and four data sets, including Foundation Medicine Inc, The Cancer Genome Atlas, International Cancer Genome Consortium, and the Oncology Research Information Exchange Network. We leveraged RNA sequencing to evaluate immune signatures. We curated literature reporting clinical outcomes of patients harboring PD-L1 or PD-L2 SVs. RESULTS Using data sets encompassing 300,000 tumors, we curated 486 cases with SVs in PD-L1 and PD-L2 and observed consistent breakpoint patterns, or hotspots. Leveraging The Cancer Genome Atlas, we observed significant upregulation in PD-L1 expression and signatures for interferon signaling, macrophages, T cells, and immune cell proliferation in samples harboring PD-L1 or PD-L2 SVs. Retrospective review of 12 studies that identified patients with SVs in PD-L1 or PD-L2 revealed > 50% (52/71) response rate to PD-1 immunotherapy with durable responses. CONCLUSION Our findings show that the 3′-UTR is frequently affected, and that SVs are associated with increased expression of ligands and immune signatures. Retrospective evidence from curated studies suggests this genomic alteration could help identify candidates for PD-1/PD-L1 immunotherapy. We expect these findings will better define PD-L1 and PD-L2 SVs in cancer and lend support for prospective clinical trials to target these alterations.
Details
- Title: Subtitle
- Pan-cancer Landscape of Programmed Death Ligand-1 and Programmed Death Ligand-2 Structural Variations
- Creators
- Emily L. Hoskins - The Ohio State UniversityEric Samorodnitsky - The Ohio State UniversityMichele R. Wing - The Ohio State UniversityJulie W. Reeser - The Ohio State UniversityJulia F. Hopkins - Foundation Medicine Inc, Cambridge, MAKarthikeyan Murugesan - Foundation Medicine Inc, Cambridge, MAZheng Kuang - Foundation Medicine Inc, Cambridge, MARaven Vella - The Ohio State UniversityLeah Stein - The Ohio State UniversityZachary Risch - The Ohio State UniversityLianbo Yu - The Ohio State UniversitySerifat Adebola - The Ohio State UniversityAnoosha Paruchuri - The Ohio State UniversityJohn Carpten - Department of Translational Genomics, Keck School of Medicine, University of Southern California, Los Angeles, CAJad Chahoud - Moffitt Cancer CenterStephen Edge - Roswell Park Cancer InstituteJill Kolesar - University of KentuckyMartin McCarter - Division of Surgical Oncology, Department of Surgery, University of Colorado School of Medicine, Aurora, COKenneth G. Nepple - University of IowaMatthew Reilley - University of VirginiaCourtney Scaife - University of UtahAbhishek Tripathi - Stephenson Cancer Center, Oklahoma City, OKNancy Single - The Ohio State UniversityRichard S.P. Huang - Foundation Medicine Inc, Cambridge, MALee A. Albacker - Foundation Medicine Inc, Cambridge, MASameek Roychowdhury - The Ohio State University
- Resource Type
- Journal article
- Publication Details
- JCO precision oncology, Vol.7(7), p.e2200300
- DOI
- 10.1200/PO.22.00300
- PMID
- 36623238
- PMCID
- PMC9928630
- ISSN
- 2473-4284
- eISSN
- 2473-4284
- Language
- English
- Date published
- 01/2023
- Academic Unit
- Pharmaceutical Sciences and Experimental Therapeutics; Urology
- Record Identifier
- 9984357452102771
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