부산대학교 도서관

Keywords: paraganglioma; pheochromocytoma; hypoxia; metastasis; programmed death-ligand 1; CD8-positive lymphocytes; succinate dehydrogenase; HIF2[alpha] Abstract Metastatic pheochromocytoma and paraganglioma (PPGL) have poor prognosis and limited therapeutic options. The recent advent of immunotherapies showing remarkable clinical efficacies against various cancer types offers the possibility of novel opportunities also for metastatic PPGL. Most PPGLs are pathogenically linked to inactivating mutations in genes encoding different succinate dehydrogenase (SDH) subunits. This causes activation of the hypoxia-inducible factor 2 (HIF2)-mediated transcriptional program in the absence of decreased intratumoral oxygen levels, a phenomenon known as pseudohypoxia. Genuine hypoxia in a tumor creates an immunosuppressive tumor microenvironment. However, the impact of pseudohypoxia in the immune landscape of tumors remains largely unexplored. In this study, tumoral expression of programmed death-ligand 1 (PD-L1) and HIF2[alpha] and tumor infiltration of CD8 T lymphocytes (CTLs) were examined in PPGL specimens from 102 patients. We assessed associations between PD-L1, CTL infiltration, HIF2[alpha] expression, and the mutational status of SDH genes. Our results show that high PD-L1 expression levels in tumor cells and CTL tumor infiltration were more frequent in metastatic than nonmetastatic PPGL. However, this phenotype was negatively associated with SDH mutations and high HIF2[alpha] protein expression. These data were validated by analysis of mRNA levels of genes expressing PD-L1, CD8, and HIF2[alpha] in PPGL included in The Cancer Genome Atlas database. Further, PD-L1 and CD8 expression was lower in norepinephrine than epinephrine-secreting PPGL. This in silico analysis also revealed the low PD-L1 or CD8 expression levels in tumors with inactivating mutations in VHL or activating mutations in the HIF2[alpha]-coding gene, EPAS1, which, together with SDH-mutated tumors, comprise the pseudohypoxic molecular subtype of PPGL. These findings suggest that pseudohypoxic tumor cells induce extrinsic signaling toward the immune cells promoting the development of an immunosuppressive environment. It also provides compelling support to explore the differential response of metastatic PPGL to immune checkpoint inhibitors. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland. Article Note: No conflicts of interest were declared. CAPTION(S): Figure S1. Schematic representation of primary and MPPGL tumor samples analyzed by immunohistochemistry with indicated antibodies Byline: Lucía Celada, Tamara Cubiella, Jaime San-Juan-Guardado, Gala Gutiérrez, Brenda Beiguela, Raúl Rodriguez, María Poch, Aurora Astudillo, Ana Grijalba, Paula Sánchez-Sobrino, Maria Tous, Elena Navarro, Teresa Serrano, Miguel Paja, Nuria Valdés, María-Dolores Chiara