Tumor immune microenvironment of primary prostate cancer with and without germline mutations in homologous recombination repair genes.

Aberrations in homologous recombination repair (HRR) genes are emerging as important biomarkers for personalized treatment in prostate cancer (PCa). HRR deficiency (HRD) could affect the tumor immune microenvironment (TIME), potentially contributing to differential responses to poly ADP-ribose polym...

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Detalles Bibliográficos
Autores: Trigos, Anna Sofia, Pasam, Anupama, Banks, Patricia, Wallace, Roslyn, Guo, Christina, Keam, Simon, Thorne, Heather, kConFab, Mitchell, Catherine, Lade, Stephen, Clouston, David, Hakansson, Alexander, Liu, Yang, Blyth, Benjamin, Murphy, Declan, Lawrentschuk, Nathan, Bolton, Damien, Moon, Daniel, Darcy, Phil, Haupt, Ygal, Williams, Scott G, Castro, Elena, Olmos, David, Goode, David, Neeson, Paul, Sandhu, Shahneen
Tipo de recurso: artículo
Fecha de publicación:2022
País:España
Institución:Instituto de Salud Carlos III (ISCIII)
Repositorio:Repisalud
Idioma:inglés
OAI Identifier:oai:repisalud.isciii.es:20.500.12105/18564
Acceso en línea:http://hdl.handle.net/20.500.12105/18564
Access Level:acceso abierto
Palabra clave:gene expression profiling
genetic markers
prostatic neoplasms
tumor microenvironment
Germ-Line Mutation
Humans
Immune Checkpoint Inhibitors
Male
Prostatic Neoplasms
Recombinational DNA Repair
Tumor Microenvironment
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spelling Tumor immune microenvironment of primary prostate cancer with and without germline mutations in homologous recombination repair genes.Trigos, Anna SofiaPasam, AnupamaBanks, PatriciaWallace, RoslynGuo, ChristinaKeam, SimonThorne, HeatherkConFabMitchell, CatherineLade, StephenClouston, DavidHakansson, AlexanderLiu, YangBlyth, BenjaminMurphy, DeclanLawrentschuk, NathanBolton, DamienMoon, DanielDarcy, PhilHaupt, YgalWilliams, Scott GCastro, ElenaOlmos, DavidGoode, DavidNeeson, PaulSandhu, Shahneengene expression profilinggenetic markersprostatic neoplasmstumor microenvironmentGerm-Line MutationHumansImmune Checkpoint InhibitorsMaleProstatic NeoplasmsRecombinational DNA RepairTumor MicroenvironmentAberrations in homologous recombination repair (HRR) genes are emerging as important biomarkers for personalized treatment in prostate cancer (PCa). HRR deficiency (HRD) could affect the tumor immune microenvironment (TIME), potentially contributing to differential responses to poly ADP-ribose polymerase (PARP) inhibitors and immune checkpoint inhibitors. Spatial distribution of immune cells in a range of cancers identifies novel disease subtypes and is related to prognosis. In this study we aimed to determine the differences in the TIME of PCa with and without germline (g) HRR mutations. We performed gene expression analysis, multiplex immunohistochemistry of T and B cells and quantitative spatial analysis of PCa samples from 36 patients with gHRD and 26 patients with sporadic PCa. Samples were archival tumor tissue from radical prostatectomies with the exception of one biopsy. Results were validated in several independent cohorts. Although the composition of the T cell and B cells was similar in the tumor areas of gHRD-mutated and sporadic tumors, the spatial profiles differed between these cohorts. We describe two T-cell spatial profiles across primary PCa, a clustered immune spatial (CIS) profile characterized by dense clusters of CD4+ T cells closely interacting with PD-L1+ cells, and a free immune spatial (FIS) profile of CD8+ cells in close proximity to tumor cells. gHRD tumors had a more T-cell inflamed microenvironment than sporadic tumors. The CIS profile was mainly observed in sporadic tumors, whereas a FIS profile was enriched in gHRD tumors. A FIS profile was associated with lower Gleason scores, smaller tumors and longer time to biochemical recurrence and metastasis. gHRD-mutated tumors have a distinct immune microenvironment compared with sporadic tumors. Spatial profiling of T-cells provides additional information beyond T-cell density and is associated with time to biochemical recurrence, time to metastasis, tumor size and Gleason scores.20242024-02-2720222022-01-0120222022-01-01research articlehttp://purl.org/coar/resource_type/c_2df8fbb1VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articlehttp://hdl.handle.net/20.500.12105/18564reponame:Repisaludinstname:Instituto de Salud Carlos III (ISCIII)Inglésengopen accesshttp://purl.org/coar/access_right/c_abf2Attribution-NonCommercial 4.0 Internationalhttp://creativecommons.org/licenses/by-nc/4.0/info:eu-repo/semantics/openAccessoai:repisalud.isciii.es:20.500.12105/185642026-06-12T12:43:37Z
dc.title.none.fl_str_mv Tumor immune microenvironment of primary prostate cancer with and without germline mutations in homologous recombination repair genes.
title Tumor immune microenvironment of primary prostate cancer with and without germline mutations in homologous recombination repair genes.
spellingShingle Tumor immune microenvironment of primary prostate cancer with and without germline mutations in homologous recombination repair genes.
Trigos, Anna Sofia
gene expression profiling
genetic markers
prostatic neoplasms
tumor microenvironment
Germ-Line Mutation
Humans
Immune Checkpoint Inhibitors
Male
Prostatic Neoplasms
Recombinational DNA Repair
Tumor Microenvironment
title_short Tumor immune microenvironment of primary prostate cancer with and without germline mutations in homologous recombination repair genes.
title_full Tumor immune microenvironment of primary prostate cancer with and without germline mutations in homologous recombination repair genes.
title_fullStr Tumor immune microenvironment of primary prostate cancer with and without germline mutations in homologous recombination repair genes.
title_full_unstemmed Tumor immune microenvironment of primary prostate cancer with and without germline mutations in homologous recombination repair genes.
title_sort Tumor immune microenvironment of primary prostate cancer with and without germline mutations in homologous recombination repair genes.
dc.creator.none.fl_str_mv Trigos, Anna Sofia
Pasam, Anupama
Banks, Patricia
Wallace, Roslyn
Guo, Christina
Keam, Simon
Thorne, Heather
kConFab
Mitchell, Catherine
Lade, Stephen
Clouston, David
Hakansson, Alexander
Liu, Yang
Blyth, Benjamin
Murphy, Declan
Lawrentschuk, Nathan
Bolton, Damien
Moon, Daniel
Darcy, Phil
Haupt, Ygal
Williams, Scott G
Castro, Elena
Olmos, David
Goode, David
Neeson, Paul
Sandhu, Shahneen
author Trigos, Anna Sofia
author_facet Trigos, Anna Sofia
Pasam, Anupama
Banks, Patricia
Wallace, Roslyn
Guo, Christina
Keam, Simon
Thorne, Heather
kConFab
Mitchell, Catherine
Lade, Stephen
Clouston, David
Hakansson, Alexander
Liu, Yang
Blyth, Benjamin
Murphy, Declan
Lawrentschuk, Nathan
Bolton, Damien
Moon, Daniel
Darcy, Phil
Haupt, Ygal
Williams, Scott G
Castro, Elena
Olmos, David
Goode, David
Neeson, Paul
Sandhu, Shahneen
author_role author
author2 Pasam, Anupama
Banks, Patricia
Wallace, Roslyn
Guo, Christina
Keam, Simon
Thorne, Heather
kConFab
Mitchell, Catherine
Lade, Stephen
Clouston, David
Hakansson, Alexander
Liu, Yang
Blyth, Benjamin
Murphy, Declan
Lawrentschuk, Nathan
Bolton, Damien
Moon, Daniel
Darcy, Phil
Haupt, Ygal
Williams, Scott G
Castro, Elena
Olmos, David
Goode, David
Neeson, Paul
Sandhu, Shahneen
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv
dc.subject.none.fl_str_mv gene expression profiling
genetic markers
prostatic neoplasms
tumor microenvironment
Germ-Line Mutation
Humans
Immune Checkpoint Inhibitors
Male
Prostatic Neoplasms
Recombinational DNA Repair
Tumor Microenvironment
topic gene expression profiling
genetic markers
prostatic neoplasms
tumor microenvironment
Germ-Line Mutation
Humans
Immune Checkpoint Inhibitors
Male
Prostatic Neoplasms
Recombinational DNA Repair
Tumor Microenvironment
description Aberrations in homologous recombination repair (HRR) genes are emerging as important biomarkers for personalized treatment in prostate cancer (PCa). HRR deficiency (HRD) could affect the tumor immune microenvironment (TIME), potentially contributing to differential responses to poly ADP-ribose polymerase (PARP) inhibitors and immune checkpoint inhibitors. Spatial distribution of immune cells in a range of cancers identifies novel disease subtypes and is related to prognosis. In this study we aimed to determine the differences in the TIME of PCa with and without germline (g) HRR mutations. We performed gene expression analysis, multiplex immunohistochemistry of T and B cells and quantitative spatial analysis of PCa samples from 36 patients with gHRD and 26 patients with sporadic PCa. Samples were archival tumor tissue from radical prostatectomies with the exception of one biopsy. Results were validated in several independent cohorts. Although the composition of the T cell and B cells was similar in the tumor areas of gHRD-mutated and sporadic tumors, the spatial profiles differed between these cohorts. We describe two T-cell spatial profiles across primary PCa, a clustered immune spatial (CIS) profile characterized by dense clusters of CD4+ T cells closely interacting with PD-L1+ cells, and a free immune spatial (FIS) profile of CD8+ cells in close proximity to tumor cells. gHRD tumors had a more T-cell inflamed microenvironment than sporadic tumors. The CIS profile was mainly observed in sporadic tumors, whereas a FIS profile was enriched in gHRD tumors. A FIS profile was associated with lower Gleason scores, smaller tumors and longer time to biochemical recurrence and metastasis. gHRD-mutated tumors have a distinct immune microenvironment compared with sporadic tumors. Spatial profiling of T-cells provides additional information beyond T-cell density and is associated with time to biochemical recurrence, time to metastasis, tumor size and Gleason scores.
publishDate 2022
dc.date.none.fl_str_mv 2022
2022-01-01
2022
2022-01-01
2024
2024-02-27
dc.type.none.fl_str_mv research article
http://purl.org/coar/resource_type/c_2df8fbb1
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv http://hdl.handle.net/20.500.12105/18564
url http://hdl.handle.net/20.500.12105/18564
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution-NonCommercial 4.0 International
http://creativecommons.org/licenses/by-nc/4.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution-NonCommercial 4.0 International
http://creativecommons.org/licenses/by-nc/4.0/
eu_rights_str_mv openAccess
dc.source.none.fl_str_mv reponame:Repisalud
instname:Instituto de Salud Carlos III (ISCIII)
instname_str Instituto de Salud Carlos III (ISCIII)
reponame_str Repisalud
collection Repisalud
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,81155

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