Blockade of T-cell receptor with Ig and ITIM domains elicits potent antitumor immunity in naturally occurring HBV-related HCC in mice

Background and Aims Chronic HBV infection is the leading cause of HCC and 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 T-cell immunoreceptor with Ig and ITIM domains (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-induced HCC, TGF-beta-activated kinase 1 knockout-induced HCC, HCC in a stelic animal model, or 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-alpha, and interferon-gamma (IFN-gamma) 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-alpha and IFN-gamma 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 antitumor activity of CD8(+) T cells during the progression of HBV-related HCC in a spontaneous HCC mouse model.