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

• Published in: Nature (London) Vol. 551; no. 7680; pp. 340 - 345
• Main Authors: Shalapour, Shabnam, Lin, Xue-Jia, Bastian, Ingmar N., Brain, John, Burt, Alastair D., Aksenov, Alexander A., Vrbanac, Alison F., Li, Weihua, Perkins, Andres, 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
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 16-11-2017; Nature Publishing Group
• Subjects: 38/23; 38/39; 38/91; 631/250/251; 631/67/580; 64/60; 82/51; 82/58; 96/106; 96/21; 96/31; Animals; B7-H1 Antigen - metabolism; Carcinoma, Hepatocellular - etiology; Carcinoma, Hepatocellular - immunology; Carcinoma, Hepatocellular - pathology; CD8 Antigens - deficiency; Cell Proliferation; Clone Cells - cytology; Clone Cells - immunology; Disease Progression; Female; Gastrointestinal Microbiome; Health aspects; Humanities and Social Sciences; Humans; Immune Tolerance - immunology; Immunoglobulin A - immunology; Immunoglobulin A - metabolism; Immunoglobulins; Inflammation - etiology; Inflammation - immunology; Inflammation - pathology; Interleukin-10 - metabolism; Liver cancer; 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; multidisciplinary; 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; Prevention; Science; T-Lymphocytes, Cytotoxic - cytology; T-Lymphocytes, Cytotoxic - immunology
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature24302

IgA
+
B cells expressing programmed death ligand 1 (PD-L1) and interleukin 10 accumulate in the inflamed livers of humans and mice with non-alcoholic fatty liver disease where they promote the progression to hepatocellular carcinoma by limiting the local activation of PD-1-expressing CD8
+
T cells.
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.
Increased cancer risk in fatty livers
Cancer progression beyond the early stages is thought to be caused in some cases by adaptive immunity, but its role remains controversial. In this study, Michael Karin and colleagues show that PD-L1-expressing IgA
+
B cells accumulate in the inflamed livers of humans and mice with non-alcoholic fatty liver disease. The inflammation-induced IgA
+
cells promote the progression to hepatocellular carcinoma by suppressing liver cytotoxic CD8
+
T cells that prevent the emergence of this aggressive tumour.