Breakdown of adaptive immunotolerance induces hepatocellular carcinoma in HBsAg-tg mice

Lu Zong, Hui Peng, Cheng Sun, Fenglei Li, Meijuan Zheng, Yongyan Chen, Haiming Wei, Rui Sun and Zhigang Tian ()
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Lu Zong: University of Science and Technology of China
Hui Peng: University of Science and Technology of China
Cheng Sun: University of Science and Technology of China
Fenglei Li: University of Science and Technology of China
Meijuan Zheng: The First Affiliated Hospital of Anhui Medical University
Yongyan Chen: University of Science and Technology of China
Haiming Wei: University of Science and Technology of China
Rui Sun: University of Science and Technology of China
Zhigang Tian: University of Science and Technology of China

Nature Communications, 2019, vol. 10, issue 1, 1-14

Abstract: Abstract Hepatitis B virus (HBV) can induce chronic inflammation, cirrhosis, and eventually hepatocellular carcinoma (HCC). Despite evidence suggesting a link between adaptive immunity and HBV-related diseases in humans, the immunopathogenic mechanisms involved are seldom described. Here we show that expression of TIGIT, a promising immune checkpoint in tumor immunotherapy, increases with age on hepatic CD8+ T cells in HBsAg-transgenic (HBs-tg) mice whose adaptive immune system is tolerant to HBsAg. TIGIT blockade or deficiency leads to chronic hepatitis and fibrosis, along with the emergence of functional HBsAg-specific cytotoxic T lymphocytes (CTLs), suggesting adaptive immune tolerance could be broken by TIGIT blockade or deficiency. Importantly, HBsAg vaccination further induces nonresolving inflammation and HCC in a CD8+ T cell-dependent manner in TIGIT-blocked or -deficient HBs-tg mice. Therefore, CD8+ T cells play an important role in adaptive immunity-mediated tumor progression and TIGIT is critical in maintenance of liver tolerance by keeping CTLs in homeostatic balance.

Date: 2019
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DOI: 10.1038/s41467-018-08096-8

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