The Impact of Interferon Gamma Receptor Expression on the Mechanism of Escape From Host Immune Surveillance in Hepatocellular Carcinoma

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Abstract
Interferon gamma (IFN-γ) plays an important role in host defense mechanism and participates in the progression of chronic liver disease. IFN-γ exerts its pleiotrophic effects by transcriptional regulation of expression of numerous genes, such as major histocompatibility complex (MHC) class I and Fas, through interaction with IFN-γ receptor (IFN-γ-R). Although hepatocytes in normal liver express weak or no IFN-γ-R, those in acute and chronic liver disease up-regulate its expression. A study using IFN-γ-R α-chain knock-out mice revealed the actions of IFN-γ on tumor cells as an extrinsic tumor-suppressor mechanism. However, it is unclear whether or how hepatocellular carcinoma (HCC) blocks the signal transduction of IFN-γ to evade host immune surveillance. We examined the expression of IFN-γ-R and IFN-γ-inducible genes in 44 cases with HCC using real-time reverse-transcriptase polymerase chain reaction (RT-PCR) and immunohistochemistry. In noncancerous liver tissues (n = 38), IFN-γ-R expression on the cell surface was up-regulated in 27 cases. In IFN-γ-R-negative cases (n = 15), tumor size was larger (P = .032), serum α-fetoprotein (AFP) level was higher (P = .001), intrahepatic and extrahepatic metastasis was more common (P = .044 and .013, respectively), and Ki-67 labeling index (LI) was higher (P = .041), compared with IFN-γ-R-positive cases. Accordingly, the evasion mechanism may play an important role in progression, especially metastasis, in HCC. The significant correlation between the status of IFN-γ-R and the expression of Fas and MHC implies that the loss of IFN-γ-R might contribute to the mechanism of escape from host immune rejection in HCC.