Abstract 4027: Recurrent gains of CD274 (PD-L1) and PDCD1LG2 (PD-L2) provide a genetic basis for PD-1 ligand expression in a subset of solid tumors
Authors: Gjini Evisa , Pak Christine , Kelly Alyssa , Shi Yuling , Lindeman Neal , Kuo Frank , Freeman Gordon , Ligon Azra , Hodi Stephen , Shipp Margaret , Rodig Scott 
Published: July 2016

Abstract
Background: A subset of malignant tumors are immunogenic but avoid immune surveillance through ectopic expression of the programmed cell death 1 ligands, PD-L1 and PD-L2, that bind PD-1 on effector T-cells to inhibit T-cell activation, a phenotype that is reversible with PD-1 blockade. Co-amplification and co-gain of CD274 (PD-L1) and PDCD1LG2 (PD-L2) on chromosome 9p24.1 provide a genetic basis for PD-1 ligand expression by Reed-Sternberg cells in classical Hodgkin lymphoma, a tumor highly sensitive to PD-1 blockade. We sought to determine whether copy number alterations of CD274 and PDCD1LG2 are a mechanism of PD-1 ligand expression in other tumor types.
Methods: We surveyed data derived from a clinically-deployed next generation sequencing assay (OncoPanel) to identify tumors with evidence of selective copy gain of genes located at 9p24.1. Formalin-fixed paraffin-embedded biopsy specimens from available cases were reviewed for tumor content, immunostained for PD-L1, and analyzed with custom probes targeting the CD274 and PDCD1LG2 loci and a commercial probe targeting the centromere of chromosome 9 by flourescence in situ hybridization (FISH).
Results: Review of NGS data revealed 171 of 7,070 clinical samples (2.4%) with evidence for selective copy gain of CD274 and/or PDCD1LG2. Tissue was available for analysis in 73 cases, of which 55 were successfully analyzed. Co-amplification and co-gain of CD274 and PDCD1LG2 were observed for 20 (36%) and 18 (33%) of cases, respectively. Polysomy 9 and disomy 9 were observed among 9 (16%) and 2 (4%) cases, respectively. Genetic abnormalities associated with chromosome 9 loss were observed among the remaining cases 6 (11%). PD-L1 IHC revealed positive staining of tumor cells in 36 (65%) cases. Among cases with co-amplification/gain of CD274 and PDCD1LG2, a subset (Co-Amp: 36%; Co-Gain: 28%) exhibited moderate to high PD-L1 expression in significant percentages of tumor cells (Tumor H-score &gt; 50). Tumor types with high PD-L1 expression in the context of co-amplification/gain included carcinomas of the head and neck, bladder, and cervix.
Conclusions: Review of over 7000 tumors analyzed by a clinically-deployed NGS platform identifies CD274 and PDCD1LG2 copy gain in a low percentage of a variety of solid tumor types, a subset of which has a corresponding increase of PD-L1 expression. These data suggest that copy gain of CD274 and PDCD1LG2 contributes to PD-1 ligand expression in a subset of solid tumors beyond classical Hodgkin lymphoma.
Citation Format: Evisa Gjini, Christine Pak, Alyssa Kelly, Yuling Shi, Neal Lindeman, Frank Kuo, Gordon Freeman, Azra Ligon, Stephen Hodi, Margaret Shipp, Scott Rodig. Recurrent gains of CD274 (PD-L1) and PDCD1LG2 (PD-L2) provide a genetic basis for PD-1 ligand expression in a subset of solid tumors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4027.