Programmed cell death ligands expression in pheochromocytomas (PCC) and paragangliomas (PGL): Relationship with the hypoxic response and malignant behaviour.

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11597 Background: The hypoxic response underlies the pathogenesis and malignant behaviour of PCC/PGL. Regulation of PD-1 receptor-ligand signalling, a therapeutically actionable driver of the anti-tumour immune response, is a hypoxic-driven trait across malignancies. We evaluated the prognostic role of PD ligands in association with biomarkers of hypoxia and angiogenesis in patients with PCC/PGL. Methods: Tissue microarrays sections including consecutive cases of PCC/PGL diagnosed between 1983-2011 were stained for PD-L1 & 2, Ki-67, hypoxia inducible factor 1a (Hif-1a), Carbonic Anhydrase IX (CaIX), Vascular Endothelial Growth Factor-A (VEGF-A). Candidate biomarkers were assessed for correlation with clinical variables including overall survival. Results: In total, 100 patients, 10% malignant, 64% PCC, 29% familial with a median tumour size of 4.7 cm (range 1-14) were included. Median follow-up was 4.7 years. PD-L1 expression was observed in 18% of cases and was independent of adverse pathological features including capsular (CI), vascular invasion (VI), necrosis (N) and expression of biomarkers of hypoxia. We observed a trend towards association with malignancy (p = 0.08). PD-L2 expression was found in 16% of tumors. PD-L2 overexpression strongly correlated with CI, VI, N (p < 0.01) and malignant behaviour (p = 0.009) and was associated with stronger Hif-1a and CaIX immunolabeling (p < 0.01). PD-L2 but not PD-L1 expression was predictive of shorter survival (162 versus 309 months, HR 3.1 95%CI 1.1-9.2, Log-rank p = 0.03). Gene set enrichment analysis on the TGCA PCC/PGL RNA-seq dataset (n = 184) revealed a positive correlation between PD-L2 and a number of transcripts involved in angiogenesis and immunity including Interleukin-6 (Pearson R = 0.57) and CD-8a (R = 0.56). Conclusions: We report for the first time PD-1 ligands expression in PCC/PGL with a distinctive prognostic and clinicopathologic role. These findings support a potential therapeutic role for PD-1/PD-L1 targeted checkpoint inhibitors in these tumors.