LAUSR

Graphical abstract Figure. No Caption available. ABSTRACT Check point inhibitor anti‐PD1 antibody produced some efficacy in Hepatocellular Carcinoma (HCC) patients previously treated with sorafenib. Unfortunately, HCC patients with hepatitis B virus (HBV) infection did not respond as well as uninfected patients. Previously, Second mitochondria‐derived activator of caspases (SMAC) mimetics‐the antagonist for inhibitor of apoptosis proteins (IAPs) can rapidly reduce serum hepatitis B virus DNA in animal model. APG‐1387 is a novel SMAC‐mimetic, small molecule inhibitor targeting inhibitor of apoptosis proteins (IAPs). In our study, firstly, we found that HCC patients with copy number alteration of cIAP1, cIAP2, and XIAP had a dismal prognosis. Then, we discovered that APG‐1387 alone could induce apoptosis of PLC/PRF/5 which was HBV positive both in‐vitro and in‐vivo. Furthermore, we found that APG‐1387 significantly up‐regulated the expression of calreticulin and HLA‐DR in PLC/PRF/5 via activating non‐classic NF‐&kgr;B pathway. Also, compared to vehicle group, APG‐1387 increased NK cell counts by 5 folds in PLC/PRF/5 xenograft model. In‐vitro, APG‐1387 positively regulated T cells by reducing Treg differentiation and down‐regulating PD1 expression in CD4 T cell. Moreover, APG‐1387 had no impact on memory T cells. Consequently, our results suggest that APG1387 could be a good candidate to combine with anti‐PD1 antibody treatment to overcome low responds of check point inhibitors in HBV positive HCC.