Pan-cancer Landscape of Programmed Death Ligand-1 and Programmed Death Ligand-2 Structural Variations.

Abstract

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 (<i>CD274</i>) and PD-L2 (<i>PDCD1LG2</i>) have been observed in cancer, but the comprehensive landscape is unknown. Here, we describe the genomic landscape of <i>PD-L1</i> and <i>PD-L2</i> SVs, their potential impact on the tumor microenvironment, and evidence that patients with these alterations can benefit from immunotherapy. We analyzed sequencing data from cancer cases with <i>PD-L1</i> and <i>PD-L2</i> 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 <i>PD-L1</i> or <i>PD-L2</i> SVs. 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 <i>PD-L1</i> expression and signatures for interferon signaling, macrophages, T cells, and immune cell proliferation in samples harboring <i>PD-L1</i> or <i>PD-L2</i> SVs. Retrospective review of 12 studies that identified patients with SVs in <i>PD-L1</i> or <i>PD-L2</i> revealed > 50% (52/71) response rate to PD-1 immunotherapy with durable responses. 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 <i>PD-L1</i> and <i>PD-L2</i> SVs in cancer and lend support for prospective clinical trials to target these alterations.