![]() ![]() However, almost 20% of tumors are malignant with the potential to recur and spread systemically, with negative implications for prognostic outlook. Surgical resection, the mainstay of treatment in PCC/PGL, is curative in most patients. ![]() Phaeochromocytomas (PCCs) and paragangliomas (PGLs) are rare catecholamine-producing neuroendocrine tumors (NETs) deriving from adrenal (PCC) or extra-adrenal (PGL) chromaffin tissue. These findings provide a rationale for the development of anti PD-1 therapies in malignant PCC/PGL. 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. 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. The molecular mechanisms underlying immune evasion in malignant phaeochromocytomas and paragangliomas (PCC/PGL) are poorly understood. These findings support a potential therapeutic role for PD-1/PD-L1 targeted checkpoint inhibitors in these tumors. ![]() We report for the first time PD ligands expression in PCC/PGL with a distinctive prognostic, clinico-pathologic and immuno-biologic role. GSEA on TGCA samples confirmed enrichment of transcripts involved in hypoxia and anti-cancer immunity. 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). 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. In total, 100 patients, 10% malignant, 64% PCC, 29% familial with median tumor size of 4.7 cm (range 1–14) were included. 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). 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 evaluated the prognostic role of PD ligands in association with biomarkers of hypoxia and angiogenesis in patients with 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. The hypoxic response underlies the pathogenesis and malignant behavior of PCC/PGL. ![]()
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February 2023
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