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

Lookup NU author(s): Dr John Brain, Professor Alastair BurtORCiD, Professor Quentin AnsteeORCiD

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This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC 4.0).

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 metadata

Author(s): Shalapour S, Lin XJ, Bastian IN, Brain J, Burt AD, Aksenov AA, Vrbanac AF, Li W, Perkins A, Matsutani T, Zhong Z, Dhar D, Navas-Molina JA, Xu J, Loomba R, Downes M, Yu RT, Evans RM, Dorrestein PC, Knight R, Benner C, Anstee QM, Karin M

Publication type: Article

Publication status: Published

Journal: Nature

Year: 2017

Volume: 551

Issue: 7680

Pages: 340-345

Print publication date: 16/11/2017

Online publication date: 08/11/2017

Acceptance date: 22/09/2017

Date deposited: 22/11/2017

ISSN (print): 0028-0836

ISSN (electronic): 1476-4687

Publisher: Nature Publishing Group

URL: http://doi.org/10.1038/nature24302

DOI: 10.1038/nature24302

PubMed id: 29144460

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