Inflammation-induced IgA+ cells dismantle anti-liver cancer immunity
Open accessAbstract
The role of adaptive immunity in early cancer development is controversial. Here we show that chronic inflammation and fibrosis in humans and mice with non-alcoholic fatty liver disease is accompanied by accumulation of liver-resident immunoglobulin-A-producing (IgA+) cells. These cells also express programmed death ligand 1 (PD-L1) and interleukin-10, and directly suppress liver cytotoxic CD8+ T lymphocytes, which prevent emergence of hepatocellular carcinoma and express a limited repertoire of T-cell receptors against tumour-associated antigens. Whereas CD8+ T-cell ablation accelerates hepatocellular carcinoma, genetic or pharmacological interference with IgA+ cell generation attenuates liver carcinogenesis and induces cytotoxic T-lymphocyte-mediated regression of established hepatocellular carcinoma. These findings establish the importance of inflammation-induced suppression of cytotoxic CD8+ T-lymphocyte activation as a tumour-promoting mechanism.
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Immunosuppressive IgA+ B cells are accumulated in MASH-related HCC and can dismantle anti-cancer immunity by suppressing cytotoxic CD8+ T cells.
“We also reveal that immunosuppressive IgA+ B cells are accumulated in MASH-related HCC and can dismantle anti-cancer immunity by suppressing cytotoxic CD8+ T cells [20].”
From Single-cell transcriptome reveals the reprogramming of immune microenvironment during the transition from MASH to HCC (2025) · cites this paper as [20]
These plasma cells are immunosuppressive plasma cells in MASH-related HCC.
“which we had previously proved to be immunosuppressive plasma cells in MASH-related HCC [20].”
From Single-cell transcriptome reveals the reprogramming of immune microenvironment during the transition from MASH to HCC (2025) · cites this paper as [20]
IgA+ cells are immunosuppressive plasma cells dismantling anti-liver cancer immunity, which are different from regulatory B cells.
“Particularly, we have proved that IgA+ cells are immunosuppressive plasma cells dismantling anti-liver cancer immunity [20], which are different from regulatory B cells.”
From Single-cell transcriptome reveals the reprogramming of immune microenvironment during the transition from MASH to HCC (2025) · cites this paper as [20]
Chronic inflammation and fibrosis in humans and mice with NAFLD are accompanied by liver-resident IgA-producing PD-L1-positive cells suppressing efficient anti-liver cancer immune responses.
“Chronic inflammation and fibrosis in humans and mice with NAFLD were accompanied by liver-resident immunoglobulin A (IgA)-producing programmed death-ligand 1-positive cells suppressing efficient anti-liver cancer immune responses.24”
From Intestinal B cells license metabolic T-cell activation in NASH microbiota/antigen-independently and contribute to fibrosis by IgA-FcR signalling (2023) · cites this paper as [24]
In mice and humans with NASH, liver-resident IgA+ cells suppress the protective role of CD8+ cytotoxic T cells, leading to HCC.
“In mice and humans with NASH, liver‐resident IgA+ cells suppress the protective role of CD8+ cytotoxic T cells leading to HCC.( 70 )”
From The Emerging Role of B Cells in the Pathogenesis of NAFLD (2021) · cites this paper as [70]
IgA+ B cells inhibit the activation and cytotoxic activity of CD8+ T cells through expression of PD-L1 and production of IL-10.
“Mechanistically, IgA+ B cells inhibit the activation and cytotoxic activity of CD8+ T cells through expression of programmed death‐ligand 1 (PD‐L1) and production of the immunosuppressive cytokine, IL‐10.( 70 )”
From The Emerging Role of B Cells in the Pathogenesis of NAFLD (2021) · cites this paper as [70]
Inflammation-induced IgA+ B cells disrupt the antitumor immune response during NASH-induced HCC in MUP-μPA mice fed an HFD.
“Inflammation‐induced IgA+ B cells seem to disrupt the antitumor immune response during NASH‐induced HCC, as shown in MUP‐μPA mice fed an HFD.( 70 )”
From The Emerging Role of B Cells in the Pathogenesis of NAFLD (2021) · cites this paper as [70]
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Self-citation
- Authors
- Shalapour, S., Lin, X.-J., Bastian, I. N., Brain, J., Burt, A. D., Aksenov, A. A., Vrbanac, A. F., Li, W., Perkins, A., Matsutani, T., Zhong, Z., Dhar, D., Navas-Molina, J. A., Xu, J., Loomba, R., Downes, M., Yu, R. T., Evans, R. M., Dorrestein, P. C., Knight, R., Benner, C., Anstee, Q. M., & Karin, M.
- Affiliations
- University of California San Diego (US)
- Jinan University (CN)
- Newcastle University (GB)
- The University of Adelaide (AU)
- Repertoire Genesis Incorporated (Japan) (JP)
- Salk Institute for Biological Studies (US)
- Corresponding author
- Shalapour, Shabnam
- Karin, Michael
- ORCID
- Shalapour, Shabnam
- Lin, Xue-Jia
- Bastian, Ingmar N.
- Burt, Alastair D.
- Aksenov, Alexander A.
- Vrbanac, Alison F.
- Li, Weihua
- Matsutani, Takaji
- Zhong, Zhenyu
- Dhar, Debanjan
- Navas-Molina, Jose A.
- Xu, Jun
- Loomba, Rohit
- Downes, Michael
- Yu, Ruth T.
- Evans, Ronald M.
- Dorrestein, Pieter C.
- Knight, Rob
- Benner, Christopher
- Anstee, Quentin M.
- Karin, Michael
- Venue
- Nature
- Published
- 2017-11-08
- Volume
- 551
- Issue
- 7680
- Pages
- 340-345
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC5884449
- OpenAlex
- W2767554904
- Cited by
- 589
- References
- 73
- Citations by year
- 2026: 56 · 2025: 70 · 2024: 79 · 2023: 65 · 2022: 90 · 2021: 72 · 2020: 61 · 2019: 55 · 2018: 37 · 2017: 4
- FWCI
- 18.93
- Type
- journal article
- Language
- en
- Update notices
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Adelaide Research & Scholarship (AR&S) (University of Adelaide) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institute for Health and Care Research (CL-2013-01-002)
- National Institutes of Health (1s10rr029121-01, AI043477, CA118165)
- Medical Research Council (MR/N005872/1)
- National Institute on Alcohol Abuse and Alcoholism (U01AA022614)
- National Cancer Institute (R01CA118165, R01CA127923, R01CA198103, P01CA128814)
- National Institute of General Medical Sciences (P41GM103484)
- National Institute of Allergy and Infectious Diseases (R01AI043477, R37AI043477)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK106419)
- National Institute of Environmental Health Sciences (P42ES010337)
- National Center for Research Resources (S10-RR029121)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Health Sciences › Medicine › Hepatology › Hepatocellular Carcinoma Treatment and Prognosis
- Keywords
- IgA+ B cells, non-alcoholic fatty liver disease, hepatocellular carcinoma, chronic liver inflammation, liver fibrosis, PD-L1, IL-10, PD-1, CD8+ T cells, T cell suppression, adaptive immunity, tumor immunosuppression, T cell receptor repertoire, tumor regression
- MeSH terms
- Gastrointestinal Microbiome, Animals, Clone Cells, Female, Carcinoma, Hepatocellular, Humans, Immunoglobulin A, Immune Tolerance, Inflammation, Liver Cirrhosis, Liver Neoplasms, Lymphocyte Activation, Male, Plasma Cells, T-Lymphocytes, Cytotoxic, Interleukin-10, CD8 Antigens, Disease Progression, Cell Proliferation, Mice, B7-H1 Antigen, Non-alcoholic Fatty Liver Disease
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