TIGIT blockade elicits potent anti-tumor immunity in naturally occurring hepatitis B virus-related hepatocellular carcinoma in mice

ABSTRACT: Background and Aims: Chronic hepatitis B virus (HBV) infection is the leading cause of hepatocellular carcinoma (HCC) and is a serious health problem in China, East Asia, and North African countries. Effective treatment of HBV-related HCC is currently unavailable. This study evaluated the therapeutic potential of TIGIT blockade in HBV-related HCC. Approach and Results: A mouse model of spontaneous HBV-related HCC was generated by replacing wild-type hepatocytes with HBsAg+ hepatocytes (namely HBs-HepR mice). The tumors in HBs-HepR mice were inflammation-associated HCC, similar to HBV-related HCC in patients, which was distinguished from other HCC mouse models, such as diethylnitrosamine (DEN)-induced HCC, Tak1-knockout-induced HCC, HCC in stelic animal model (STAM), or nonalcoholic steatohepatitis (NASH)-induced HCC. HCC in HBs-HepR mice was characterized by an increased number of CD8+T cells whereas the production of IL-2, TNF-α, and IFN-γ by intrahepatic CD8+T cells was decreased. Increased expression of TIGIT on CD8+T cells was responsible for functional exhaustion. The therapeutic effect of TIGIT blockade was investigated at the early and middle stages of HCC progression in HBs-HepR mice. TIGIT blockade reinvigorated intrahepatic CD8+T cells with increased TNF-α and IFN-γ production and an increased number of CD8+T cells in tumors, thereby slowing the development of HCC in HBs-HepR mice. Blocking PD-L1 did not show direct therapeutic effects or synergize with TIGIT blockade. Conclusions: Blockade of TIGIT alone enhanced the anti-tumor activity of CD8+T cells during the progression of HBV-related HCC in a spontaneous HCC mouse model.

ORGANISM(S): Mus musculus

PROVIDER: GSE209856 | GEO | 2022/12/31

REPOSITORIES: GEO