Inflammation-induced IgA+ cells dismantle anti-liver cancer immunity

Shabnam Shalapour; Xue-Jia Lin; Ingmar N Bastian; John Brain; Alastair D Burt; Alexander A Aksenov; Alison F Vrbanac; Weihua Li; Andres Perkins; Takaji Matsutani; Zhenyu Zhong; Debanjan Dhar; Jose A Navas-Molina; Jun Xu; Rohit Loomba; Michael Downes; Ruth T Yu; Ronald M Evans; Pieter C Dorrestein; Rob Knight; Christopher Benner; Quentin M Anstee; Michael Karin

doi:10.1038/nature24302

Inflammation-induced IgA+ cells dismantle anti-liver cancer immunity

Nature. 2017 Nov 16;551(7680):340-345. doi: 10.1038/nature24302. Epub 2017 Nov 8.

Authors

Shabnam Shalapour¹, Xue-Jia Lin^{1

2}, Ingmar N Bastian¹, John Brain³, Alastair D Burt⁴, Alexander A Aksenov⁵, Alison F Vrbanac⁶, Weihua Li¹, Andres Perkins¹, Takaji Matsutani⁷, Zhenyu Zhong¹, Debanjan Dhar¹, Jose A Navas-Molina⁶, Jun Xu⁸, Rohit Loomba⁹, Michael Downes¹⁰, Ruth T Yu¹⁰, Ronald M Evans¹⁰, Pieter C Dorrestein^{5

11}, Rob Knight^{6

11}, Christopher Benner⁸, Quentin M Anstee³, Michael Karin^{1

11}

Affiliations

¹ Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California San Diego (UCSD), 9500 Gilman Drive, La Jolla, California 92093, USA.
² Biomedical Translational Research Institute and The First Affiliated Hospital, Jinan University, Guangzhou 510632, China.
³ Liver Research Group, Institute of Cellular Medicine, The Medical School, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
⁴ Faculty of Health and Medical Sciences, University of Adelaide, South Australia 5005, Australia.
⁵ Collaborative Mass Spectrometry Innovation Center, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego (UCSD), 9500 Gilman Drive, La Jolla, California 92093, USA.
⁶ Departments of Pediatrics and Computer Science & Engineering, University of California San Diego (UCSD), 9500 Gilman Drive, La Jolla, California 92093, USA.
⁷ R&D Department, Repertoire Genesis Incorporation, Ibaraki, Osaka 567-0085, Japan.
⁸ Department of Medicine, University of California San Diego (UCSD), 9500 Gilman Drive, La Jolla, California 92093, USA.
⁹ NAFLD Research Center, Division of Gastroenterology, Department of Medicine, University of California San Diego (UCSD), La Jolla, California 92093, USA.
¹⁰ Gene Expression Laboratory, Howard Hughes Medical Institute, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.
¹¹ Center for Microbiome Innovation, University of California San Diego (UCSD), La Jolla, California 92093, USA.

Abstract

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
B7-H1 Antigen / metabolism
CD8 Antigens / deficiency
Carcinoma, Hepatocellular / etiology
Carcinoma, Hepatocellular / immunology*
Carcinoma, Hepatocellular / pathology
Cell Proliferation
Clone Cells / cytology
Clone Cells / immunology
Disease Progression
Female
Gastrointestinal Microbiome
Humans
Immune Tolerance / immunology*
Immunoglobulin A / immunology*
Immunoglobulin A / metabolism
Inflammation / etiology
Inflammation / immunology*
Inflammation / pathology
Interleukin-10 / metabolism
Liver Cirrhosis / complications
Liver Cirrhosis / immunology
Liver Cirrhosis / metabolism
Liver Cirrhosis / pathology
Liver Neoplasms / etiology
Liver Neoplasms / immunology*
Liver Neoplasms / pathology
Lymphocyte Activation
Male
Mice
Non-alcoholic Fatty Liver Disease / complications*
Non-alcoholic Fatty Liver Disease / immunology*
Non-alcoholic Fatty Liver Disease / metabolism
Non-alcoholic Fatty Liver Disease / pathology
Plasma Cells / immunology
Plasma Cells / metabolism
T-Lymphocytes, Cytotoxic / cytology
T-Lymphocytes, Cytotoxic / immunology

Substances

B7-H1 Antigen
CD8 Antigens
CD8 antigen, alpha chain
Immunoglobulin A
Interleukin-10

Abstract

Publication types

MeSH terms

Substances

Grants and funding