Essential roles of B cell subsets in the progression of MASLD and HCC
Background & Aims: Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death. Metabolic dysfunction-associated steatotic liver disease (MASLD) is a significant cause of HCC. Current treatment options for HCC are very limited. Recent evidence highlights B cells as key...
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2024-12-01
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| Series: | JHEP Reports |
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| author | Nataliia Petriv Huizhen Suo Inga Hochnadel Kai Timrott Nina Bondarenko Lavinia Neubert Elena Reinhard Nils Jedicke Patrick Kaufhold Carlos Alberto Guzmán Ralf Lichtinghagen Michael P. Manns Heike Bantel Tetyana Yevsa |
| author_facet | Nataliia Petriv Huizhen Suo Inga Hochnadel Kai Timrott Nina Bondarenko Lavinia Neubert Elena Reinhard Nils Jedicke Patrick Kaufhold Carlos Alberto Guzmán Ralf Lichtinghagen Michael P. Manns Heike Bantel Tetyana Yevsa |
| author_sort | Nataliia Petriv |
| collection | DOAJ |
| description | Background & Aims: Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death. Metabolic dysfunction-associated steatotic liver disease (MASLD) is a significant cause of HCC. Current treatment options for HCC are very limited. Recent evidence highlights B cells as key drivers in MASLD progression toward HCC. However, it remains unclear whether multiple B cell populations or a distinct B cell subset regulates inflammatory responses during liver disease progression. The scope of this study was to define protumorigenic B cell subsets in MASLD and HCC. Methods: Multicolor flow cytometry, immunohistochemistry, and immunofluorescence analyses were performed to investigate B cell populations locally (in liver tissue) and systemically (in the blood) in mice with MASLD (n = 6) and HCC (n = 5–6). The results obtained in mice were also verified in patients with MASLD (n = 19) and HCC (n = 16). Results: Our study revealed an increase of two regulatory B cell (Breg) subsets, CD19+B220+CD5+CD1d+ (p <0.0001) and CD19-B220+CD5+CD1d- (p <0.0001), both of which highly overexpress IgM/IgD, PD-L1, and IL-10, in the livers of mice with MASLD and HCC. Furthermore, we showed that B-cell depletion therapy in combination with a Listeria-based vaccine decreased CD19-B220+CD5+CD1d- Bregs (p = 0.0103), and improved survival of mice with HCC. We also found CD19+CD5+IL-10+ (p = 0.0167), CD19+CD5+PD-L1+ (p = 0.0333) and CD19+CD5+IgM+IgD+ (p = 0.0317) B cells in human HCCs. In addition, strong overexpression of IgM/IgD, PD-L1, IL-10, were detected on non-switched memory B cells (p = 0.0049) and plasmablasts (p = 0.0020). The examination of blood samples obtained from patients with MASLD showed an increase of total B cells expressing IL-10 (p <0.0001) and IgM/IgD (p = 0.3361), CD19+CD20+CD5+CD1d+ Bregs (p = 0.6424) and CD19+CD20+CD27+ non-switched memory B cells (p = 0.0003). Conclusions: Our results provide novel insights into the protumorigenic roles of several B cell subsets, the specific targeting of which could abrogate the progression of liver disease. Impact and implications: Hepatocellular carcinoma (HCC) is the primary liver cancer with a constantly rising mortality rate. Metabolic dysfunction-associated steatotic liver disease (MASLD) is an emerging important cause of HCC. Current treatment options for HCC are limited and there is a high risk of recurrence. The study aims to identify new therapeutic strategies by exploring the immunological aspects of MASLD and HCC. Our findings extend the current knowledge on the role of B cells in the progression of MASLD and HCC. This study emphasizes the involvement of IgM+IgD+ regulatory B cells (Bregs) in malignant liver disease progression. These Bregs characterized by a high expression of PD-L1, IL-10, IgM, and IgD. Two other B cell subsets with immunosuppressive phenotype have been found in the study in murine liver disease - plasmablasts and non-switched memory B cells. Targeting these B cells could lead to more effective treatments of HCC. |
| format | Article |
| id | doaj-art-ef1620cb3a1343f29ec24dfc1537cb8e |
| institution | DOAJ |
| issn | 2589-5559 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | JHEP Reports |
| spelling | doaj-art-ef1620cb3a1343f29ec24dfc1537cb8e2025-08-20T02:48:58ZengElsevierJHEP Reports2589-55592024-12-0161210118910.1016/j.jhepr.2024.101189Essential roles of B cell subsets in the progression of MASLD and HCCNataliia Petriv0Huizhen Suo1Inga Hochnadel2Kai Timrott3Nina Bondarenko4Lavinia Neubert5Elena Reinhard6Nils Jedicke7Patrick Kaufhold8Carlos Alberto Guzmán9Ralf Lichtinghagen10Michael P. Manns11Heike Bantel12Tetyana Yevsa13Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School (MHH), Hannover, GermanyDepartment of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School (MHH), Hannover, GermanyDepartment of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School (MHH), Hannover, GermanyDepartment of General-, Visceral and Transplantation Surgery, MHH, Hannover, GermanyDepartment of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School (MHH), Hannover, Germany; Department of Pathological Anatomy, Forensic Medicine and Pathological Physiology, Dnipro State Medical University, Dnipro, Ukraine; Institute of Pathology, MHH, Hannover, GermanyInstitute of Pathology, MHH, Hannover, GermanyDepartment of Vaccinology and Applied Microbiology, Helmholtz Centre for Infection Research, Braunschweig, GermanyDepartment of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School (MHH), Hannover, GermanyDepartment of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School (MHH), Hannover, GermanyDepartment of Vaccinology and Applied Microbiology, Helmholtz Centre for Infection Research, Braunschweig, GermanyDepartment of Clinical Chemistry, MHH, Hannover, GermanyDepartment of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School (MHH), Hannover, GermanyDepartment of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School (MHH), Hannover, GermanyDepartment of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School (MHH), Hannover, Germany; Corresponding author. Address: Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Carl-Neuberg Str. 1, 30625 Hannover, Germany. Tel.: +49-511-532-83164; Fax: +49-511-532-5692.Background & Aims: Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death. Metabolic dysfunction-associated steatotic liver disease (MASLD) is a significant cause of HCC. Current treatment options for HCC are very limited. Recent evidence highlights B cells as key drivers in MASLD progression toward HCC. However, it remains unclear whether multiple B cell populations or a distinct B cell subset regulates inflammatory responses during liver disease progression. The scope of this study was to define protumorigenic B cell subsets in MASLD and HCC. Methods: Multicolor flow cytometry, immunohistochemistry, and immunofluorescence analyses were performed to investigate B cell populations locally (in liver tissue) and systemically (in the blood) in mice with MASLD (n = 6) and HCC (n = 5–6). The results obtained in mice were also verified in patients with MASLD (n = 19) and HCC (n = 16). Results: Our study revealed an increase of two regulatory B cell (Breg) subsets, CD19+B220+CD5+CD1d+ (p <0.0001) and CD19-B220+CD5+CD1d- (p <0.0001), both of which highly overexpress IgM/IgD, PD-L1, and IL-10, in the livers of mice with MASLD and HCC. Furthermore, we showed that B-cell depletion therapy in combination with a Listeria-based vaccine decreased CD19-B220+CD5+CD1d- Bregs (p = 0.0103), and improved survival of mice with HCC. We also found CD19+CD5+IL-10+ (p = 0.0167), CD19+CD5+PD-L1+ (p = 0.0333) and CD19+CD5+IgM+IgD+ (p = 0.0317) B cells in human HCCs. In addition, strong overexpression of IgM/IgD, PD-L1, IL-10, were detected on non-switched memory B cells (p = 0.0049) and plasmablasts (p = 0.0020). The examination of blood samples obtained from patients with MASLD showed an increase of total B cells expressing IL-10 (p <0.0001) and IgM/IgD (p = 0.3361), CD19+CD20+CD5+CD1d+ Bregs (p = 0.6424) and CD19+CD20+CD27+ non-switched memory B cells (p = 0.0003). Conclusions: Our results provide novel insights into the protumorigenic roles of several B cell subsets, the specific targeting of which could abrogate the progression of liver disease. Impact and implications: Hepatocellular carcinoma (HCC) is the primary liver cancer with a constantly rising mortality rate. Metabolic dysfunction-associated steatotic liver disease (MASLD) is an emerging important cause of HCC. Current treatment options for HCC are limited and there is a high risk of recurrence. The study aims to identify new therapeutic strategies by exploring the immunological aspects of MASLD and HCC. Our findings extend the current knowledge on the role of B cells in the progression of MASLD and HCC. This study emphasizes the involvement of IgM+IgD+ regulatory B cells (Bregs) in malignant liver disease progression. These Bregs characterized by a high expression of PD-L1, IL-10, IgM, and IgD. Two other B cell subsets with immunosuppressive phenotype have been found in the study in murine liver disease - plasmablasts and non-switched memory B cells. Targeting these B cells could lead to more effective treatments of HCC.http://www.sciencedirect.com/science/article/pii/S2589555924001939Metabolic dysfunction-associated steatotic liver diseaseNon-alcoholic fatty liver diseaseHepatocellular carcinomaB cellsB regulatory cellsMemory B cells |
| spellingShingle | Nataliia Petriv Huizhen Suo Inga Hochnadel Kai Timrott Nina Bondarenko Lavinia Neubert Elena Reinhard Nils Jedicke Patrick Kaufhold Carlos Alberto Guzmán Ralf Lichtinghagen Michael P. Manns Heike Bantel Tetyana Yevsa Essential roles of B cell subsets in the progression of MASLD and HCC JHEP Reports Metabolic dysfunction-associated steatotic liver disease Non-alcoholic fatty liver disease Hepatocellular carcinoma B cells B regulatory cells Memory B cells |
| title | Essential roles of B cell subsets in the progression of MASLD and HCC |
| title_full | Essential roles of B cell subsets in the progression of MASLD and HCC |
| title_fullStr | Essential roles of B cell subsets in the progression of MASLD and HCC |
| title_full_unstemmed | Essential roles of B cell subsets in the progression of MASLD and HCC |
| title_short | Essential roles of B cell subsets in the progression of MASLD and HCC |
| title_sort | essential roles of b cell subsets in the progression of masld and hcc |
| topic | Metabolic dysfunction-associated steatotic liver disease Non-alcoholic fatty liver disease Hepatocellular carcinoma B cells B regulatory cells Memory B cells |
| url | http://www.sciencedirect.com/science/article/pii/S2589555924001939 |
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