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Published on: September 25, 2018
Pan-cancer Landscape of Programmed Death Ligand-1 and Programmed Death Ligand-2 Structural Variations
Emily L Hoskins1,2, Eric Samorodnitsky1, Michele R Wing1
1Comprehensive Cancer Center and James Cancer Hospital, The Ohio State University, Columbus, OH.
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.
Insights
Structural variations in PD-L1 and PD-L2 genes are linked to increased immune cell activity and a high response rate to PD-1 immunotherapy in cancer patients. These findings may help identify candidates for immunotherapy.
Area of Science:
- Genomics and Cancer Biology
- Immunotherapy and Cancer Treatment
Background:
- Programmed cell death protein-1 (PD-1) receptor-ligand interactions are crucial targets for immunotherapies across numerous cancer types.
- Current biomarkers for immunotherapy response include microsatellite instability, tumor mutational burden, and PD-L1 immunohistochemistry.
- Structural variations (SVs) in PD-L1 (CD274) and PD-L2 (PDCD1LG2) are known in cancer but their comprehensive landscape and clinical implications remain underexplored.
Purpose of the Study:
- To comprehensively map the genomic landscape of structural variations (SVs) in PD-L1 and PD-L2 genes in cancer.
- To investigate the potential impact of these SVs on the tumor microenvironment and immune signatures.
- To evaluate the clinical benefit of PD-1/PD-L1 immunotherapy in patients with PD-L1 or PD-L2 SVs.
Main Methods:
- Analysis of sequencing data from 486 cancer cases with PD-L1 and PD-L2 SVs, drawn from 22 publications and four major datasets (Foundation Medicine, TCGA, ICGC, ONCO-RN).
- Utilized RNA sequencing to assess immune signatures, including interferon signaling and immune cell infiltration.
- Curated literature to identify and analyze clinical outcomes of patients with PD-L1 or PD-L2 SVs.
Main Results:
- Identified consistent breakpoint patterns (hotspots) within PD-L1 and PD-L2 genes across a large cohort of 300,000 tumors.
- Observed significant upregulation of PD-L1 expression and immune signatures (interferon signaling, macrophages, T cells, immune proliferation) in tumors with PD-L1/PD-L2 SVs.
- Retrospective analysis of 12 studies showed a >50% response rate (52/71 patients) to PD-1 immunotherapy among patients with PD-L1 or PD-L2 SVs, with durable responses observed.
Conclusions:
- Structural variations, frequently affecting the 3'-UTR, are associated with increased PD-L1/PD-L2 ligand expression and heightened immune signatures.
- Genomic alterations in PD-L1/PD-L2 may serve as a predictive biomarker for identifying patients who can benefit from PD-1/PD-L1 immunotherapy.
- These findings warrant further investigation through prospective clinical trials to target these specific genomic alterations in cancer treatment.
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