Hepatic CD4 T Cells Predict Hepatocellular Carcinoma Risk on Metabolic Dysfunction‐Associated Steatohepatitis Patients

Autores
Rodriguez, Emilse; Simon, Peter; Dhooge, Sabrina de Lourdes; Fernandez, Marina Laura; Calafat, Patricia; Kurpis, María; Nuñez, Nicolás; Prieto, Jhon; Saborowski, Anna; Vogel, Arndt; Debes, José Daniel; Balderramo, Domingo Cesar; Boonstra, Andre; Romagnoli, Pablo Alberto
Año de publicación
2025
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Background & Aims: Metabolic dysfunction‐associated steatohepatitis (MASH) increasingly drives hepatocellular carcinoma(HCC) development. We characterized inflammatory infiltrates in liver biopsies from MASH patients who developed HCCversus controls to identify predictive immune signatures.Method: Formalin‐fixed paraffin‐embedded (FFPE) liver biopsies from MASH patients were categorized as pre‐HCC MASH(n = 10) or control MASH (n = 13) by the ESCALON consortium. Standardized histological analysis and multiplexed immunohistochemistrywere performed targeting CD4, CD8, PD1, PDL1, FoxP3, CXCR6, CD3, CD68, and CD20 using a PhenoImagerFusion scanner. Single‐cell RNA‐seq datasets characterized hepatic CD4 T cell heterogeneity. Clinical parameters measuredincluded ALT, AST, GGT, alkaline phosphatase, platelets, and INR.Results: Pre‐HCC MASH showed inflammation extending from portal to periportal areas versus portal‐only distribution incontrols. Analysis of 291,908 cells revealed significantly higher CD4þ density (p = 0.0243) and CD4þPD1þ cells (p = 0.017) inpre‐HCC patients, while CD8þ and regulatory T cell densities remained unchanged. Single‐cell RNA‐seq identified potentialphenotypic shifts from Th1 cytotoxicity toward tissue‐repair and Th17 CD4þ T cells in MASH livers. Combined immunologicaland clinical variables (sex, age, CD4þ T cell numbers, ALT, alkaline phosphatase and platelets) achieved excellent predictiveperformance (ROC‐AUC = 0.944) for HCC development.Conclusions: Increase in liver CD4þ T cell infiltration characterizes MASH‐to‐HCC progression. These immune signaturescombined with clinical parameters demonstrate remarkable predictive value for identifying high‐risk MASH patients.
Fil: Rodriguez, Emilse. Hospital Privado Centro Médico de Córdoba; Argentina
Fil: Simon, Peter. Medizinische Hochschule Hannover; Alemania
Fil: Dhooge, Sabrina de Lourdes. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas; Argentina
Fil: Fernandez, Marina Laura. Hospital Privado Centro Médico de Córdoba; Argentina
Fil: Calafat, Patricia. Hospital Privado Centro Médico de Córdoba; Argentina
Fil: Kurpis, María. Hospital Privado Centro Médico de Córdoba; Argentina
Fil: Nuñez, Nicolás. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas; Argentina
Fil: Prieto, Jhon. Centro de enfermedades hepáticas y digestivas; Colombia
Fil: Saborowski, Anna. Medizinische Hochschule Hannover; Alemania
Fil: Vogel, Arndt. Medizinische Hochschule Hannover; Alemania. University of Toronto; Canadá
Fil: Debes, José Daniel. University of Minnesota; Estados Unidos. Erasmus University;
Fil: Balderramo, Domingo Cesar. Hospital Privado Centro Médico de Córdoba; Argentina
Fil: Boonstra, Andre. Erasmus University (erasmus University);
Fil: Romagnoli, Pablo Alberto. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Instituto Universitario de Ciencias Biomédicas de Córdoba; Argentina
Materia
CANCER
CD4
LIVER
SINGLE
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/278805
Acceder
id CONICETDig_533ecfed124d5bb0b04d3e38508c1dfb
oai_identifier_str oai:ri.conicet.gov.ar:11336/278805
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Hepatic CD4 T Cells Predict Hepatocellular Carcinoma Risk on Metabolic Dysfunction‐Associated Steatohepatitis PatientsRodriguez, EmilseSimon, PeterDhooge, Sabrina de LourdesFernandez, Marina LauraCalafat, PatriciaKurpis, MaríaNuñez, NicolásPrieto, JhonSaborowski, AnnaVogel, ArndtDebes, José DanielBalderramo, Domingo CesarBoonstra, AndreRomagnoli, Pablo AlbertoCANCERCD4LIVERSINGLEhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Background & Aims: Metabolic dysfunction‐associated steatohepatitis (MASH) increasingly drives hepatocellular carcinoma(HCC) development. We characterized inflammatory infiltrates in liver biopsies from MASH patients who developed HCCversus controls to identify predictive immune signatures.Method: Formalin‐fixed paraffin‐embedded (FFPE) liver biopsies from MASH patients were categorized as pre‐HCC MASH(n = 10) or control MASH (n = 13) by the ESCALON consortium. Standardized histological analysis and multiplexed immunohistochemistrywere performed targeting CD4, CD8, PD1, PDL1, FoxP3, CXCR6, CD3, CD68, and CD20 using a PhenoImagerFusion scanner. Single‐cell RNA‐seq datasets characterized hepatic CD4 T cell heterogeneity. Clinical parameters measuredincluded ALT, AST, GGT, alkaline phosphatase, platelets, and INR.Results: Pre‐HCC MASH showed inflammation extending from portal to periportal areas versus portal‐only distribution incontrols. Analysis of 291,908 cells revealed significantly higher CD4þ density (p = 0.0243) and CD4þPD1þ cells (p = 0.017) inpre‐HCC patients, while CD8þ and regulatory T cell densities remained unchanged. Single‐cell RNA‐seq identified potentialphenotypic shifts from Th1 cytotoxicity toward tissue‐repair and Th17 CD4þ T cells in MASH livers. Combined immunologicaland clinical variables (sex, age, CD4þ T cell numbers, ALT, alkaline phosphatase and platelets) achieved excellent predictiveperformance (ROC‐AUC = 0.944) for HCC development.Conclusions: Increase in liver CD4þ T cell infiltration characterizes MASH‐to‐HCC progression. These immune signaturescombined with clinical parameters demonstrate remarkable predictive value for identifying high‐risk MASH patients.Fil: Rodriguez, Emilse. Hospital Privado Centro Médico de Córdoba; ArgentinaFil: Simon, Peter. Medizinische Hochschule Hannover; AlemaniaFil: Dhooge, Sabrina de Lourdes. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas; ArgentinaFil: Fernandez, Marina Laura. Hospital Privado Centro Médico de Córdoba; ArgentinaFil: Calafat, Patricia. Hospital Privado Centro Médico de Córdoba; ArgentinaFil: Kurpis, María. Hospital Privado Centro Médico de Córdoba; ArgentinaFil: Nuñez, Nicolás. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas; ArgentinaFil: Prieto, Jhon. Centro de enfermedades hepáticas y digestivas; ColombiaFil: Saborowski, Anna. Medizinische Hochschule Hannover; AlemaniaFil: Vogel, Arndt. Medizinische Hochschule Hannover; Alemania. University of Toronto; CanadáFil: Debes, José Daniel. University of Minnesota; Estados Unidos. Erasmus University;Fil: Balderramo, Domingo Cesar. Hospital Privado Centro Médico de Córdoba; ArgentinaFil: Boonstra, Andre. Erasmus University (erasmus University);Fil: Romagnoli, Pablo Alberto. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Instituto Universitario de Ciencias Biomédicas de Córdoba; ArgentinaWiley2025-12info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/278805Rodriguez, Emilse; Simon, Peter; Dhooge, Sabrina de Lourdes; Fernandez, Marina Laura; Calafat, Patricia; et al.; Hepatic CD4 T Cells Predict Hepatocellular Carcinoma Risk on Metabolic Dysfunction‐Associated Steatohepatitis Patients; Wiley; United European Gastroenterology Journal; 2025; 12-2025; 1-122050-64062050-6414CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://onlinelibrary.wiley.com/doi/10.1002/ueg2.70159info:eu-repo/semantics/altIdentifier/doi/10.1002/ueg2.70159info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-nd/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2026-02-26T10:09:20Zoai:ri.conicet.gov.ar:11336/278805instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982026-02-26 10:09:21.13CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Hepatic CD4 T Cells Predict Hepatocellular Carcinoma Risk on Metabolic Dysfunction‐Associated Steatohepatitis Patients
title Hepatic CD4 T Cells Predict Hepatocellular Carcinoma Risk on Metabolic Dysfunction‐Associated Steatohepatitis Patients
spellingShingle Hepatic CD4 T Cells Predict Hepatocellular Carcinoma Risk on Metabolic Dysfunction‐Associated Steatohepatitis Patients
Rodriguez, Emilse
CANCER
CD4
LIVER
SINGLE
title_short Hepatic CD4 T Cells Predict Hepatocellular Carcinoma Risk on Metabolic Dysfunction‐Associated Steatohepatitis Patients
title_full Hepatic CD4 T Cells Predict Hepatocellular Carcinoma Risk on Metabolic Dysfunction‐Associated Steatohepatitis Patients
title_fullStr Hepatic CD4 T Cells Predict Hepatocellular Carcinoma Risk on Metabolic Dysfunction‐Associated Steatohepatitis Patients
title_full_unstemmed Hepatic CD4 T Cells Predict Hepatocellular Carcinoma Risk on Metabolic Dysfunction‐Associated Steatohepatitis Patients
title_sort Hepatic CD4 T Cells Predict Hepatocellular Carcinoma Risk on Metabolic Dysfunction‐Associated Steatohepatitis Patients
dc.creator.none.fl_str_mv Rodriguez, Emilse
Simon, Peter
Dhooge, Sabrina de Lourdes
Fernandez, Marina Laura
Calafat, Patricia
Kurpis, María
Nuñez, Nicolás
Prieto, Jhon
Saborowski, Anna
Vogel, Arndt
Debes, José Daniel
Balderramo, Domingo Cesar
Boonstra, Andre
Romagnoli, Pablo Alberto
author Rodriguez, Emilse
author_facet Rodriguez, Emilse
Simon, Peter
Dhooge, Sabrina de Lourdes
Fernandez, Marina Laura
Calafat, Patricia
Kurpis, María
Nuñez, Nicolás
Prieto, Jhon
Saborowski, Anna
Vogel, Arndt
Debes, José Daniel
Balderramo, Domingo Cesar
Boonstra, Andre
Romagnoli, Pablo Alberto
author_role author
author2 Simon, Peter
Dhooge, Sabrina de Lourdes
Fernandez, Marina Laura
Calafat, Patricia
Kurpis, María
Nuñez, Nicolás
Prieto, Jhon
Saborowski, Anna
Vogel, Arndt
Debes, José Daniel
Balderramo, Domingo Cesar
Boonstra, Andre
Romagnoli, Pablo Alberto
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv CANCER
CD4
LIVER
SINGLE
topic CANCER
CD4
LIVER
SINGLE
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Background & Aims: Metabolic dysfunction‐associated steatohepatitis (MASH) increasingly drives hepatocellular carcinoma(HCC) development. We characterized inflammatory infiltrates in liver biopsies from MASH patients who developed HCCversus controls to identify predictive immune signatures.Method: Formalin‐fixed paraffin‐embedded (FFPE) liver biopsies from MASH patients were categorized as pre‐HCC MASH(n = 10) or control MASH (n = 13) by the ESCALON consortium. Standardized histological analysis and multiplexed immunohistochemistrywere performed targeting CD4, CD8, PD1, PDL1, FoxP3, CXCR6, CD3, CD68, and CD20 using a PhenoImagerFusion scanner. Single‐cell RNA‐seq datasets characterized hepatic CD4 T cell heterogeneity. Clinical parameters measuredincluded ALT, AST, GGT, alkaline phosphatase, platelets, and INR.Results: Pre‐HCC MASH showed inflammation extending from portal to periportal areas versus portal‐only distribution incontrols. Analysis of 291,908 cells revealed significantly higher CD4þ density (p = 0.0243) and CD4þPD1þ cells (p = 0.017) inpre‐HCC patients, while CD8þ and regulatory T cell densities remained unchanged. Single‐cell RNA‐seq identified potentialphenotypic shifts from Th1 cytotoxicity toward tissue‐repair and Th17 CD4þ T cells in MASH livers. Combined immunologicaland clinical variables (sex, age, CD4þ T cell numbers, ALT, alkaline phosphatase and platelets) achieved excellent predictiveperformance (ROC‐AUC = 0.944) for HCC development.Conclusions: Increase in liver CD4þ T cell infiltration characterizes MASH‐to‐HCC progression. These immune signaturescombined with clinical parameters demonstrate remarkable predictive value for identifying high‐risk MASH patients.
Fil: Rodriguez, Emilse. Hospital Privado Centro Médico de Córdoba; Argentina
Fil: Simon, Peter. Medizinische Hochschule Hannover; Alemania
Fil: Dhooge, Sabrina de Lourdes. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas; Argentina
Fil: Fernandez, Marina Laura. Hospital Privado Centro Médico de Córdoba; Argentina
Fil: Calafat, Patricia. Hospital Privado Centro Médico de Córdoba; Argentina
Fil: Kurpis, María. Hospital Privado Centro Médico de Córdoba; Argentina
Fil: Nuñez, Nicolás. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas; Argentina
Fil: Prieto, Jhon. Centro de enfermedades hepáticas y digestivas; Colombia
Fil: Saborowski, Anna. Medizinische Hochschule Hannover; Alemania
Fil: Vogel, Arndt. Medizinische Hochschule Hannover; Alemania. University of Toronto; Canadá
Fil: Debes, José Daniel. University of Minnesota; Estados Unidos. Erasmus University;
Fil: Balderramo, Domingo Cesar. Hospital Privado Centro Médico de Córdoba; Argentina
Fil: Boonstra, Andre. Erasmus University (erasmus University);
Fil: Romagnoli, Pablo Alberto. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Instituto Universitario de Ciencias Biomédicas de Córdoba; Argentina
description Background & Aims: Metabolic dysfunction‐associated steatohepatitis (MASH) increasingly drives hepatocellular carcinoma(HCC) development. We characterized inflammatory infiltrates in liver biopsies from MASH patients who developed HCCversus controls to identify predictive immune signatures.Method: Formalin‐fixed paraffin‐embedded (FFPE) liver biopsies from MASH patients were categorized as pre‐HCC MASH(n = 10) or control MASH (n = 13) by the ESCALON consortium. Standardized histological analysis and multiplexed immunohistochemistrywere performed targeting CD4, CD8, PD1, PDL1, FoxP3, CXCR6, CD3, CD68, and CD20 using a PhenoImagerFusion scanner. Single‐cell RNA‐seq datasets characterized hepatic CD4 T cell heterogeneity. Clinical parameters measuredincluded ALT, AST, GGT, alkaline phosphatase, platelets, and INR.Results: Pre‐HCC MASH showed inflammation extending from portal to periportal areas versus portal‐only distribution incontrols. Analysis of 291,908 cells revealed significantly higher CD4þ density (p = 0.0243) and CD4þPD1þ cells (p = 0.017) inpre‐HCC patients, while CD8þ and regulatory T cell densities remained unchanged. Single‐cell RNA‐seq identified potentialphenotypic shifts from Th1 cytotoxicity toward tissue‐repair and Th17 CD4þ T cells in MASH livers. Combined immunologicaland clinical variables (sex, age, CD4þ T cell numbers, ALT, alkaline phosphatase and platelets) achieved excellent predictiveperformance (ROC‐AUC = 0.944) for HCC development.Conclusions: Increase in liver CD4þ T cell infiltration characterizes MASH‐to‐HCC progression. These immune signaturescombined with clinical parameters demonstrate remarkable predictive value for identifying high‐risk MASH patients.
publishDate 2025
dc.date.none.fl_str_mv 2025-12
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/278805
Rodriguez, Emilse; Simon, Peter; Dhooge, Sabrina de Lourdes; Fernandez, Marina Laura; Calafat, Patricia; et al.; Hepatic CD4 T Cells Predict Hepatocellular Carcinoma Risk on Metabolic Dysfunction‐Associated Steatohepatitis Patients; Wiley; United European Gastroenterology Journal; 2025; 12-2025; 1-12
2050-6406
2050-6414
CONICET Digital
CONICET
url http://hdl.handle.net/11336/278805
identifier_str_mv Rodriguez, Emilse; Simon, Peter; Dhooge, Sabrina de Lourdes; Fernandez, Marina Laura; Calafat, Patricia; et al.; Hepatic CD4 T Cells Predict Hepatocellular Carcinoma Risk on Metabolic Dysfunction‐Associated Steatohepatitis Patients; Wiley; United European Gastroenterology Journal; 2025; 12-2025; 1-12
2050-6406
2050-6414
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/https://onlinelibrary.wiley.com/doi/10.1002/ueg2.70159
info:eu-repo/semantics/altIdentifier/doi/10.1002/ueg2.70159
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Wiley
publisher.none.fl_str_mv Wiley
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 13.176822

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