Lymphocyte exhaustion in hepatocellular carcinoma: a dynamic evolution across disease stages
BackgroundImmune checkpoint inhibitors (ICIs) have transformed cancer therapy. However, their efficacy in hepatocellular carcinoma (HCC) is limited, highlighting the need to further explore immune microenvironments and novel biomarkers. This study examined lymphocyte populations and immune checkpoin...
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Frontiers Media S.A.
2025-06-01
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| author | Carla Fuster-Anglada Carla Fuster-Anglada Carla Fuster-Anglada Josep Corominas Josep Corominas Aida Marsal Aida Marsal Neus Llarch Neus Llarch Neus Llarch Neus Llarch Gemma Iserte Gemma Iserte Gemma Iserte Marco Sanduzzi-Zamparelli Marco Sanduzzi-Zamparelli Marco Sanduzzi-Zamparelli Alejandro Forner Alejandro Forner Alejandro Forner Alejandro Forner Joana Ferrer-Fábrega Joana Ferrer-Fábrega Joana Ferrer-Fábrega Joana Ferrer-Fábrega Victor Holguin Victor Holguin Albert Morales Albert Morales Albert Morales Carolina Saavedra Maria Reig Maria Reig Maria Reig Loreto Boix Loreto Boix Montserrat Marí Montserrat Marí Montserrat Marí Alba Díaz Alba Díaz Alba Díaz Alba Díaz |
| author_facet | Carla Fuster-Anglada Carla Fuster-Anglada Carla Fuster-Anglada Josep Corominas Josep Corominas Aida Marsal Aida Marsal Neus Llarch Neus Llarch Neus Llarch Neus Llarch Gemma Iserte Gemma Iserte Gemma Iserte Marco Sanduzzi-Zamparelli Marco Sanduzzi-Zamparelli Marco Sanduzzi-Zamparelli Alejandro Forner Alejandro Forner Alejandro Forner Alejandro Forner Joana Ferrer-Fábrega Joana Ferrer-Fábrega Joana Ferrer-Fábrega Joana Ferrer-Fábrega Victor Holguin Victor Holguin Albert Morales Albert Morales Albert Morales Carolina Saavedra Maria Reig Maria Reig Maria Reig Loreto Boix Loreto Boix Montserrat Marí Montserrat Marí Montserrat Marí Alba Díaz Alba Díaz Alba Díaz Alba Díaz |
| author_sort | Carla Fuster-Anglada |
| collection | DOAJ |
| description | BackgroundImmune checkpoint inhibitors (ICIs) have transformed cancer therapy. However, their efficacy in hepatocellular carcinoma (HCC) is limited, highlighting the need to further explore immune microenvironments and novel biomarkers. This study examined lymphocyte populations and immune checkpoint dynamics in early, advanced, and post-progression HCC to better understand immune dynamics in HCC and to help identify predictive biomarkers and immune modulation strategies.MethodsTumoral and non-tumoral liver tissues were analyzed from HCC patients across early (n=25), advanced (n=22), and advanced-beyond-progression (n=15) stages. Lymphocyte profiling was performed using immunohistochemistry and flow cytometry, focusing on NK cells, T cells, and immune exhaustion markers. An exploratory analysis of this profile and its association with disease progression and recurrence was conducted.ResultsEarly HCC exhibited higher liver-resident NK (lrNK) cell densities in non-tumor regions, which diminished with advanced stages. Increased CD56+ cell infiltration in the tumor core was associated with recurrence. Tumor region showed elevated PD-1, NKG2A, and CD39 expression in CD4+ and CD8+ T cells, indicating progressive immune exhaustion. Advanced HCC stages demonstrated altered NK cell phenotypes, with reduced cytotoxic activation (CD16) and increased residency markers (CXCR6/CD69) in tumor-isolated lymphocytes.ConclusionsProgressive immune exhaustion and dysregulation of lrNK and T cells in HCC reflect the evolution of the immune microenvironment originating in the tumor and leaking into the non-tumoral liver, progressively diminishing the cytotoxic capacity of NK and T cells. CD56+ cell density and immune checkpoint profiles are potential biomarkers for therapeutic response and disease monitoring, underscoring the need for personalized immunotherapy strategies. |
| format | Article |
| id | doaj-art-b198fa2c04014bcdb96bce198ddb5f96 |
| institution | OA Journals |
| issn | 1664-3224 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj-art-b198fa2c04014bcdb96bce198ddb5f962025-08-20T02:32:33ZengFrontiers Media S.A.Frontiers in Immunology1664-32242025-06-011610.3389/fimmu.2025.16113651611365Lymphocyte exhaustion in hepatocellular carcinoma: a dynamic evolution across disease stagesCarla Fuster-Anglada0Carla Fuster-Anglada1Carla Fuster-Anglada2Josep Corominas3Josep Corominas4Aida Marsal5Aida Marsal6Neus Llarch7Neus Llarch8Neus Llarch9Neus Llarch10Gemma Iserte11Gemma Iserte12Gemma Iserte13Marco Sanduzzi-Zamparelli14Marco Sanduzzi-Zamparelli15Marco Sanduzzi-Zamparelli16Alejandro Forner17Alejandro Forner18Alejandro Forner19Alejandro Forner20Joana Ferrer-Fábrega21Joana Ferrer-Fábrega22Joana Ferrer-Fábrega23Joana Ferrer-Fábrega24Victor Holguin25Victor Holguin26Albert Morales27Albert Morales28Albert Morales29Carolina Saavedra30Maria Reig31Maria Reig32Maria Reig33Loreto Boix34Loreto Boix35Montserrat Marí36Montserrat Marí37Montserrat Marí38Alba Díaz39Alba Díaz40Alba Díaz41Alba Díaz42Pathology Department, Centro de Diagnóstico Biomédico (CDB), Liver Oncology Unit, Hospital Clinic Barcelona, Barcelona, SpainBarcelona Clinic Liver Cancer (BCLC) Group, Instituto De Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS), Barcelona, SpainCentro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, SpainBarcelona Clinic Liver Cancer (BCLC) Group, Instituto De Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS), Barcelona, SpainCentro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, SpainBarcelona Clinic Liver Cancer (BCLC) Group, Instituto De Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS), Barcelona, SpainCentro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, SpainBarcelona Clinic Liver Cancer (BCLC) Group, Instituto De Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS), Barcelona, SpainCentro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, SpainLiver Oncology Unit, Liver Unit, ICMDM, Hospital Clinic Barcelona, Barcelona, SpainFacultad de Medicina, Universitat de Barcelona, Barcelona, SpainBarcelona Clinic Liver Cancer (BCLC) Group, Instituto De Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS), Barcelona, SpainCentro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, SpainLiver Oncology Unit, Liver Unit, ICMDM, Hospital Clinic Barcelona, Barcelona, SpainBarcelona Clinic Liver Cancer (BCLC) Group, Instituto De Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS), Barcelona, SpainCentro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, SpainLiver Oncology Unit, Liver Unit, ICMDM, Hospital Clinic Barcelona, Barcelona, SpainBarcelona Clinic Liver Cancer (BCLC) Group, Instituto De Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS), Barcelona, SpainCentro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, SpainLiver Oncology Unit, Liver Unit, ICMDM, Hospital Clinic Barcelona, Barcelona, SpainFacultad de Medicina, Universitat de Barcelona, Barcelona, SpainBarcelona Clinic Liver Cancer (BCLC) Group, Instituto De Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS), Barcelona, SpainCentro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, SpainFacultad de Medicina, Universitat de Barcelona, Barcelona, SpainHepatobiliopancreatic Surgery and Liver and Pancreatic Transplantation Unit, Department of Surgery, Liver Oncology Unit, Instituto Clínic de Enfermedades Digestivas y Metabólicas (ICMDM), Hospital Clinic Barcelona, Barcelona, SpainBarcelona Clinic Liver Cancer (BCLC) Group, Instituto De Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS), Barcelona, SpainHepatobiliopancreatic Surgery and Liver and Pancreatic Transplantation Unit, Department of Surgery, Liver Oncology Unit, Instituto Clínic de Enfermedades Digestivas y Metabólicas (ICMDM), Hospital Clinic Barcelona, Barcelona, SpainBarcelona Clinic Liver Cancer (BCLC) Group, Instituto De Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS), Barcelona, SpainCentro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, SpainDepartment of Molecular and Cellular Biomedicine, Instituto de Investigaciones Biomédicas de Barcelona, Consejo Superior de Investigaciones Científicas (IIBB-CSIC), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Catalunya, SpainMedical Statistics Core Facility, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clinic Barcelona, Barcelona, SpainBarcelona Clinic Liver Cancer (BCLC) Group, Instituto De Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS), Barcelona, SpainCentro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, SpainLiver Oncology Unit, Liver Unit, ICMDM, Hospital Clinic Barcelona, Barcelona, SpainBarcelona Clinic Liver Cancer (BCLC) Group, Instituto De Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS), Barcelona, SpainCentro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, SpainBarcelona Clinic Liver Cancer (BCLC) Group, Instituto De Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS), Barcelona, SpainCentro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, SpainDepartment of Molecular and Cellular Biomedicine, Instituto de Investigaciones Biomédicas de Barcelona, Consejo Superior de Investigaciones Científicas (IIBB-CSIC), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Catalunya, SpainPathology Department, Centro de Diagnóstico Biomédico (CDB), Liver Oncology Unit, Hospital Clinic Barcelona, Barcelona, SpainBarcelona Clinic Liver Cancer (BCLC) Group, Instituto De Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS), Barcelona, SpainCentro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, SpainFacultad de Medicina, Universitat de Barcelona, Barcelona, SpainBackgroundImmune checkpoint inhibitors (ICIs) have transformed cancer therapy. However, their efficacy in hepatocellular carcinoma (HCC) is limited, highlighting the need to further explore immune microenvironments and novel biomarkers. This study examined lymphocyte populations and immune checkpoint dynamics in early, advanced, and post-progression HCC to better understand immune dynamics in HCC and to help identify predictive biomarkers and immune modulation strategies.MethodsTumoral and non-tumoral liver tissues were analyzed from HCC patients across early (n=25), advanced (n=22), and advanced-beyond-progression (n=15) stages. Lymphocyte profiling was performed using immunohistochemistry and flow cytometry, focusing on NK cells, T cells, and immune exhaustion markers. An exploratory analysis of this profile and its association with disease progression and recurrence was conducted.ResultsEarly HCC exhibited higher liver-resident NK (lrNK) cell densities in non-tumor regions, which diminished with advanced stages. Increased CD56+ cell infiltration in the tumor core was associated with recurrence. Tumor region showed elevated PD-1, NKG2A, and CD39 expression in CD4+ and CD8+ T cells, indicating progressive immune exhaustion. Advanced HCC stages demonstrated altered NK cell phenotypes, with reduced cytotoxic activation (CD16) and increased residency markers (CXCR6/CD69) in tumor-isolated lymphocytes.ConclusionsProgressive immune exhaustion and dysregulation of lrNK and T cells in HCC reflect the evolution of the immune microenvironment originating in the tumor and leaking into the non-tumoral liver, progressively diminishing the cytotoxic capacity of NK and T cells. CD56+ cell density and immune checkpoint profiles are potential biomarkers for therapeutic response and disease monitoring, underscoring the need for personalized immunotherapy strategies.https://www.frontiersin.org/articles/10.3389/fimmu.2025.1611365/fullhepatocellular carcinomalymphocytesNK cellsimmune exhaustionsorafenib |
| spellingShingle | Carla Fuster-Anglada Carla Fuster-Anglada Carla Fuster-Anglada Josep Corominas Josep Corominas Aida Marsal Aida Marsal Neus Llarch Neus Llarch Neus Llarch Neus Llarch Gemma Iserte Gemma Iserte Gemma Iserte Marco Sanduzzi-Zamparelli Marco Sanduzzi-Zamparelli Marco Sanduzzi-Zamparelli Alejandro Forner Alejandro Forner Alejandro Forner Alejandro Forner Joana Ferrer-Fábrega Joana Ferrer-Fábrega Joana Ferrer-Fábrega Joana Ferrer-Fábrega Victor Holguin Victor Holguin Albert Morales Albert Morales Albert Morales Carolina Saavedra Maria Reig Maria Reig Maria Reig Loreto Boix Loreto Boix Montserrat Marí Montserrat Marí Montserrat Marí Alba Díaz Alba Díaz Alba Díaz Alba Díaz Lymphocyte exhaustion in hepatocellular carcinoma: a dynamic evolution across disease stages Frontiers in Immunology hepatocellular carcinoma lymphocytes NK cells immune exhaustion sorafenib |
| title | Lymphocyte exhaustion in hepatocellular carcinoma: a dynamic evolution across disease stages |
| title_full | Lymphocyte exhaustion in hepatocellular carcinoma: a dynamic evolution across disease stages |
| title_fullStr | Lymphocyte exhaustion in hepatocellular carcinoma: a dynamic evolution across disease stages |
| title_full_unstemmed | Lymphocyte exhaustion in hepatocellular carcinoma: a dynamic evolution across disease stages |
| title_short | Lymphocyte exhaustion in hepatocellular carcinoma: a dynamic evolution across disease stages |
| title_sort | lymphocyte exhaustion in hepatocellular carcinoma a dynamic evolution across disease stages |
| topic | hepatocellular carcinoma lymphocytes NK cells immune exhaustion sorafenib |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1611365/full |
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