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

被引：517

作者：

Shalapour, Shabnam ^{[1
]}

Lin, Xue-Jia ^{[1
,2
,3
]}

Bastian, Ingmar N. ^{[1
]}

Brain, John ^{[4
]}

Burt, Alastair D. ^{[5
]}

Aksenov, Alexander A. ^{[6
]}

Vrbanac, Alison F. ^{[7
,8
]}

Li, Weihua ^{[1
]}

Perkins, Andres ^{[1
]}

Matsutani, Takaji ^{[9
]}

Zhong, Zhenyu ^{[1
]}

Dhar, Debanjan ^{[1
]}

Navas-Molina, Jose A. ^{[7
,8
]}

Xu, Jun ^{[10
]}

Loomba, Rohit ^{[11
]}

Downes, Michael ^{[12
]}

Yu, Ruth T. ^{[12
]}

Evans, Ronald M. ^{[12
]}

Dorrestein, Pieter C. ^{[6
,13
]}

Knight, Rob ^{[7
,8
,13
]}

Benner, Christopher ^{[10
]}

Anstee, Quentin M. ^{[4
]}

Karin, Michael ^{[1
,13
]}

机构：

[1] Univ Calif San Diego, Sch Med, Dept Pharmacol, Lab Gene Regulat & Signal Transduct, 9500 Gilman Dr, La Jolla, CA 92093 USA

[2] Jinan Univ, Biomed Translat Res Inst, Guangzhou 510632, Guangdong, Peoples R China

[3] Jinan Univ, Affiliated Hosp 1, Guangzhou 510632, Guangdong, Peoples R China

[4] Newcastle Univ, Med Sch, Inst Cellular Med, Liver Res Grp, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England

[5] Univ Adelaide, Fac Hlth & Med Sci, Adelaide, SA 5005, Australia

[6] Univ Calif San Diego, Skaggs Sch Pharm & Pharmaceut Sci, Collaborat Mass Spectrometry Innovat Ctr, 9500 Gilman Dr, La Jolla, CA 92093 USA

[7] Univ Calif San Diego, Dept Pediat, 9500 Gilman Dr, La Jolla, CA 92093 USA

[8] Univ Calif San Diego, Dept Comp Sci & Engn, 9500 Gilman Dr, La Jolla, CA 92093 USA

[9] Repertoire Genesis Inc, R&D Dept, Ibaraki, Osaka 5670085, Japan

[10] Univ Calif San Diego, Dept Med, 9500 Gilman Dr, La Jolla, CA 92093 USA

[11] Univ Calif San Diego, Dept Med, NAFLD Res Ctr, Div Gastroenterol, La Jolla, CA 92093 USA

[12] Salk Inst Biol Studies, Howard Hughes Med Inst, Gene Express Lab, 10010 North Torrey Pines Rd, La Jolla, CA 92037 USA

[13] Univ Calif San Diego, Ctr Microbiome Innovat, La Jolla, CA 92093 USA

来源：

NATURE | 2017年 / 551卷 / 7680期

基金：

美国国家卫生研究院;

关键词：

NONALCOHOLIC STEATOHEPATITIS; HEPATOCELLULAR-CARCINOMA; TARGETED DELETION; DEFICIENT MOUSE; KAPPA-B; GENE; EXPRESSION; MICE; IMMUNOTHERAPY; FIBROSIS;

D O I：

10.1038/nature24302

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];

摘要：

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.

引用

页码：340 / +

页数：30

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