Pseudohypoxia in paraganglioma and pheochromocytoma is associated with an immunosuppressive phenotype

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 pa...

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Autores: Celada, Lucía, Cubiella Victorero, Tamara, San Juan Guardado, Jaime, Gutiérrez Buey, Gala, Beiguela, Brenda, Rodriguez Aguilar, Raúl, Poch Arenas, María, Astudillo, Aurora, Grijalba, Ana, Sánchez Sobrino, Paula, Tous, Maria, Navarro, Elena, Serrano Piñol, M. Teresa, Paja, Miguel, Valdés, Nuria, Chiara, María Dolores
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2022
País:España
Institución:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/224135
Acceso en línea:https://hdl.handle.net/2445/224135
Access Level:acceso abierto
Palabra clave:Metàstasi
Classificació de tumors
Cèl·lules canceroses
Metastasis
Tumors classification
Cancer cells
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spelling Pseudohypoxia in paraganglioma and pheochromocytoma is associated with an immunosuppressive phenotypeCelada, LucíaCubiella Victorero, TamaraSan Juan Guardado, JaimeGutiérrez Buey, GalaBeiguela, BrendaRodriguez Aguilar, RaúlPoch Arenas, MaríaAstudillo, AuroraGrijalba, AnaSánchez Sobrino, PaulaTous, MariaNavarro, ElenaSerrano Piñol, M. TeresaPaja, MiguelValdés, NuriaChiara, María DoloresMetàstasiClassificació de tumorsCèl·lules cancerosesMetastasisTumors classificationCancer cellsMetastatic 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. (c) 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.John Wiley & Sons2022info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2445/224135Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))reponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglésReproducció del document publicat a: https://doi.org/10.1002/path.6026The Journal of Pathology, 2022, vol. 259, num. 1, p. 103-114https://doi.org/10.1002/path.6026cc-by-nc-nd (c) Celada, Lucía et al., 2022http://creativecommons.org/licenses/by-nc-nd/3.0/es/info:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/2241352026-05-27T06:46:51Z
dc.title.none.fl_str_mv Pseudohypoxia in paraganglioma and pheochromocytoma is associated with an immunosuppressive phenotype
title Pseudohypoxia in paraganglioma and pheochromocytoma is associated with an immunosuppressive phenotype
spellingShingle Pseudohypoxia in paraganglioma and pheochromocytoma is associated with an immunosuppressive phenotype
Celada, Lucía
Metàstasi
Classificació de tumors
Cèl·lules canceroses
Metastasis
Tumors classification
Cancer cells
title_short Pseudohypoxia in paraganglioma and pheochromocytoma is associated with an immunosuppressive phenotype
title_full Pseudohypoxia in paraganglioma and pheochromocytoma is associated with an immunosuppressive phenotype
title_fullStr Pseudohypoxia in paraganglioma and pheochromocytoma is associated with an immunosuppressive phenotype
title_full_unstemmed Pseudohypoxia in paraganglioma and pheochromocytoma is associated with an immunosuppressive phenotype
title_sort Pseudohypoxia in paraganglioma and pheochromocytoma is associated with an immunosuppressive phenotype
dc.creator.none.fl_str_mv Celada, Lucía
Cubiella Victorero, Tamara
San Juan Guardado, Jaime
Gutiérrez Buey, Gala
Beiguela, Brenda
Rodriguez Aguilar, Raúl
Poch Arenas, María
Astudillo, Aurora
Grijalba, Ana
Sánchez Sobrino, Paula
Tous, Maria
Navarro, Elena
Serrano Piñol, M. Teresa
Paja, Miguel
Valdés, Nuria
Chiara, María Dolores
author Celada, Lucía
author_facet Celada, Lucía
Cubiella Victorero, Tamara
San Juan Guardado, Jaime
Gutiérrez Buey, Gala
Beiguela, Brenda
Rodriguez Aguilar, Raúl
Poch Arenas, María
Astudillo, Aurora
Grijalba, Ana
Sánchez Sobrino, Paula
Tous, Maria
Navarro, Elena
Serrano Piñol, M. Teresa
Paja, Miguel
Valdés, Nuria
Chiara, María Dolores
author_role author
author2 Cubiella Victorero, Tamara
San Juan Guardado, Jaime
Gutiérrez Buey, Gala
Beiguela, Brenda
Rodriguez Aguilar, Raúl
Poch Arenas, María
Astudillo, Aurora
Grijalba, Ana
Sánchez Sobrino, Paula
Tous, Maria
Navarro, Elena
Serrano Piñol, M. Teresa
Paja, Miguel
Valdés, Nuria
Chiara, María Dolores
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Metàstasi
Classificació de tumors
Cèl·lules canceroses
Metastasis
Tumors classification
Cancer cells
topic Metàstasi
Classificació de tumors
Cèl·lules canceroses
Metastasis
Tumors classification
Cancer cells
description 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. (c) 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
publishDate 2022
dc.date.none.fl_str_mv 2022
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/224135
url https://hdl.handle.net/2445/224135
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: https://doi.org/10.1002/path.6026
The Journal of Pathology, 2022, vol. 259, num. 1, p. 103-114
https://doi.org/10.1002/path.6026
dc.rights.none.fl_str_mv cc-by-nc-nd (c) Celada, Lucía et al., 2022
http://creativecommons.org/licenses/by-nc-nd/3.0/es/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc-by-nc-nd (c) Celada, Lucía et al., 2022
http://creativecommons.org/licenses/by-nc-nd/3.0/es/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv John Wiley & Sons
publisher.none.fl_str_mv John Wiley & Sons
dc.source.none.fl_str_mv Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))
reponame:Dipòsit Digital de la UB
instname:Universidad de Barcelona
instname_str Universidad de Barcelona
reponame_str Dipòsit Digital de la UB
collection Dipòsit Digital de la UB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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