Abstract 761: Pan-cancer landscape and impact of PD-L1 and PD-L2 structural variation
Authors: Hoskins Emily L. , Samorodnitsky Eric , Wing Michele R. , Reeser Julie W. , Hopkins Julia , Murugesan Karthikeyan , Kuang Zheng , Stein Leah , Risch Zach , Vella Raven , Adebola Serifat , Yu Lianbo , Paruchuri Anoosha , Huang Richard S. , Albacker Lee A. , Roychowdhury Sameek 
Published: June 2022

Purpose PD-1 receptor and ligand interactions are the target of immunotherapies across 16 cancer types. Biomarkers that predict response to immunotherapy are microsatellite instability, tumor mutational burden and PD-L1 immunohistochemistry. Structural variations in PD-L1 (CD274) and PD-L2 (PDCD1LG2) have been observed across cancer, but the full landscape is unknown. Here we describe the genomic landscape of PD-L1 and PD-L2 structural variation, 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 (CD274) and PD-L2 (PDCD1LG2) structural variations across published data, The Cancer Genome Atlas (TCGA) and the Oncology Research Information Exchange Network. From TCGA we obtained copy number status through cBioPortal, gene expression using TCGABiolinks and PD-L1 structural variations identified by Kataoka et al. Gene fusions were detected in ORIEN using STAR-Fusion and Arriba. To evaluate immune signature enrichment we ran software ImSig on gene expression data, using Mann-Whitney tests to determine significant results. We curated literature of patients with structural variations in PD-L1 or PD-L2 receiving PD-1 immunotherapy.

Findings From 18 studies and datasets we curated 319 cases with structural variations in PD-L1 and PD-L2. We observed breakpoint ‘hotspots’ in the untranslated regions (UTRs) of both genes including 70 duplications, 48 deletions, 78 inversions and 106 translocations. Leveraging TCGA, we found that PD-L1 amplified tumors had significantly upregulated PD-L1 expression and signatures for interferon signaling and immune cell proliferation, compared to PD-L1 copy neutral tumors, each p &lt; 0.001. Similarly, in PD-L1 rearranged tumors we observed upregulation in PD-L1 expression and signatures for interferon signaling, macrophages, monocytes, T cells and immune cell proliferation, all p &lt; 0.001 compared to PD-L1 copy neutral tumors. Further, retrospective review of 7 studies including patients with structural variations in PD-L1 or PD-L2 revealed &gt;50% (43/77) response rate to immunotherapy.

Implications Our evaluation of PD-L1 and PD-L2 structural variations show that the 3’ UTR is affected in hotspots involving a variety of structural variations. Our findings from TCGA suggest PD-L1 structural variation may play a role in driving expression of PD-L1 and immune dysregulation. Enriched interferon signaling in PD-L1 rearranged tumors is of interest as interferon exposure is known to drive PD-L1 and PD-L2 expression. Retrospective evidence from curated studies suggest that this genomic alteration could help identify candidates for PD-1 inhibitors. Based on these findings we propose further study to optimize detection of PD-L1 and PD-L2 structural variation in cancer and design of a pan-cancer prospective clinical trial to target these alterations.

Citation Format: Emily L. Hoskins, Eric Samorodnitsky, Michele R. Wing, Julie W. Reeser, Julia Hopkins, Karthikeyan Murugesan, Zheng Kuang, Leah Stein, Zach Risch, Raven Vella, Serifat Adebola, Lianbo Yu, Anoosha Paruchuri, Richard S. Huang, Lee A. Albacker, Sameek Roychowdhury. Pan-cancer landscape and impact of PD-L1 and PD-L2 structural variation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 761.