Programmed cell death ligands expression in phaeochromocytomas and paragangliomas: Relationship with the hypoxic response, immune evasion and malignant behavior

Abstract

The hypoxic response underlies the pathogenesis and malignant behavior of PCC/PGL. Regulation of PD-1 receptor-ligand signaling, a therapeutically actionable driver of the anti-tumor 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.Tissue microarrays sections including consecutive cases diagnosed between 1983–2011 were stained for PD-L1 and 2, hypoxia inducible factor 1a (Hif-1a), Carbonic Anhydrase IX (CaIX), Vascular Endothelial Growth Factor-A (VEGF-A). We explored the biologic significance of PD ligands expression using gene set enrichment analysis (GSEA) on The Cancer Genome Atlas (TCGA) for PCC/PGL (n = 184).In total, 100 patients, 10% malignant, 64% PCC, 29% familial with median tumor size of 4.7 cm (range 1–14) were included. Median follow-up was 4.7 y. We found PD-L1 expression in 18% of PCC/PGL, which was independent of adverse pathological features including capsular (CI), vascular invasion (VI), necrosis (N) and expression of biomarkers of hypoxia. PD-L2 expression (16%) strongly correlated with CI, VI, N and malignant behavior (p < 0.05) and was associated with stronger Hif-1a and CaIX immunolabeling (p < 0.01). PD-L2 was predictive of shorter survival (162 versus 309 months, HR 3.1 95%CI 1.1–9.2, p = 0.02). GSEA on TGCA samples confirmed enrichment of transcripts involved in hypoxia and anti-cancer immunity.We report for the first time PD ligands expression in PCC/PGL with a distinctive prognostic, clinico-pathologic and immuno-biologic role. These findings support a potential therapeutic role for PD-1/PD-L1 targeted checkpoint inhibitors in these tumors.KEY MESSAGEThe molecular mechanisms underlying immune evasion in malignant phaeochromocytomas and paragangliomas (PCC/PGL) are poorly understood. This study demonstrates for the first time a distinctive immune-biologic and prognostic role of programmed death ligands 1 and 2 (PD-L1, PD-L2), two actionable drivers of the anti-cancer immune response. RNA-sequencing of tumor tissues reveals enrichment of transcripts relating to hypoxia and immune-exhaustion to explain the adverse clinical course observed in PD-L2 overexpressing tumors. These findings provide a rationale for the development of anti PD-1 therapies in malignant PCC/PGL.

Phase 2 study of pembrolizumab in patients with advanced rare cancers

“…35 Several antiangiogenic agents, such as sunitinib, pazopanib, axitinib, and cabozantinib, are under investigation. Given that PD-L1/ PD-L2 were expressed in 50% of the tumors surgically removed, 36 NPR of 43% and CBR of 75% in our study, provides a rationale for the development of pembrolizumab for these tumors.…”

Recent Advances in Histopathological and Molecular Diagnosis in Pheochromocytoma and Paraganglioma: Challenges for Predicting Metastasis in Individual Patients

“…However, the usefulness of somatostatin analogs in the treatment of patients with PPGLs has not been established, and the clinicopathological value of SSTR IHC should be validated by further studies. Surrogate markers associated with tumor immune microenvironmental factors have been studied recently, especially PD-1/PD-L1 in PPGLs (97,98). Guo et al examined PD-L1 immunoreactivity in 77 PPGL cases using an anti-PD-L1 antibody (clone E1L3N) and reported that 59.74% (46/77 cases) of PPGLs were IHC-positive for PD-L1, with high co-efficiency of Ki-67 LI, as well as the presence of hypertension (97).…”

Identification of CXCL8 as an Immune Microenvironment Regulator of Colorectal Cancer: A Bioinformatics Study Based on Cancer Genome Atlas and Gene Expression Omnibus Datasets

“…In this study, we found that CXCL8 up-regulation is negatively associated with PD-L1 (CD274) and PD-L2 (PDCD1LG2) Meanwhile, we established that the high expression of CXCL8 was positively correlated with the HIF-1α expression. Furthermore, evidence showed that HIF-1α was positively correlated with the expression of PD-L1 and PD-L2 [39,40]. Therefore, we speculated that CXCL8 may play an immunosuppressive function through the HIF-1α/PD-Ls axis.…”