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

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

Author information

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.

PMID:
29144460
PMCID:
PMC5884449
DOI:
10.1038/nature24302
[Indexed for MEDLINE]
Free PMC Article

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