Research Article
Kim Moon Yoon
Abstract
The field of hepatocellular carcinoma (HCC) immunotherapy has made progress whereas negative checkpoint regulators restrict T-cell responses. Programmed death-1 homolog (PD–1H) has been shown to suppress T–cell responses. Hepatocellular carcinoma (HCC), the most kind of primary carcinoma, is characterised by a high rate of intra-hepatic invasion. The stroma of HCC is infiltrated by myofibroblasts. we’ve antecedently shown that hepatocyte protein (HGF) secreted by human liver myofibroblasts greatly accrued the in vitro invasiveness of three human HCC cell lines. during this study we have a tendency to show that the conditioned medium (CM) from identical HCC cell lines dose-dependently stimulates HGF secretion by myofibroblasts. This result was post-transcriptional as no increase in HGF RNA was discovered. we have a tendency to show that the result of CM isn’t because of IL-1, IL-6, IGF-1, bFGF or PDGF, antecedently shown to stimulate HGF synthesis in different models. Our information demonstrate that HCC cells increase HGF secretion by liver myofibroblasts during a paracrine means that might act to boost invasion. Thus, this study aimed to determine the role of PD-1H in immunotherapy targeting HCC, the expression and prognostic value of PD-1H in HCC. Quantitative real-time PCR and immunoblotting were used to determine the expression of PD-1H in murine (MH134) and human (Huh–7) HCC cell lines. Cytotoxicity assay was performed using PD-1H siRNA transfection. The potential synergistic effect of anti-mouse CTLA-4 antibody combined with anti-mouse PD-1H blocking antibody was evaluated in the murine HCC model. The expression of PD–1H was assessed in 86 HCC tissue microarrays (TMAs) by immunohistochemistry (IHC) and quantitative real-time PCR. Associations between the PD–1H, clinicopathological variables, and survival were analyzed. Both in mouse and human, PD-1H was expressed on HCC cells. Moreover, PD-1H was significantly overexpressed in hypoxic than normoxic conditions. Cytotoxicity of CIK cells over HCC cells was significantly suppressed in a hypoxic condition, but blocking of PD-1H restored cytotoxicity of CIK cells both in normoxic and hypoxic conditions. Moreover, PD-1H blockade augmented anti-mouse CTLA-4 antibody responses in the murine HCC model (P=0.028). Finally, Kaplan-Meier curves demonstrated that patients with low PD-1H expression showed significantly prolonged overall survival (OS) than those with high PD-1H expression. These findings show that PD-1H, a novel negative immunoregulatory molecule, has functional activities that are nonredundant with other immunoglobulin superfamily members and may play a prognostic role in HCC immunotherapy.