Expression of co-stimulator 4-1BB molecule in hepatocellular carcinoma and adjacent non-tumor liver tissue and its possible role in tumor immunity

摘要

AIM: To investigate the expression of 4-1BB molecule in hepatocellular carcinoma (HCC) and its adjacent tissues.METHODS: Reverse transcription–polymerase chain reaction (RT-PCR) was used to determine the gene expression of 4-1BB in hepatocarcinoma and its adjacent tissues, and peripheral blood mononuclear cells (PBMCs) from both HCC and health control groups. Flow cytometry was used to analyse the phenotypes of T cell subsets from the blood of HCC patients and healthy volunteers, and further to determine whether 4-1BB molecules were also expressed on the surface of CD4+ and CD8+ T cells. The localization of 4-1BB proteins on tumor infiltrating T cells was determined by direct immunofluorescence cytochemical staining and detected by confocal microscopy.RESULTS: 4-1BB mRNA, which was not detectable in normal liver, was found in 19 liver tissues adjacent to tumor edge (< 1.0 cm). Low expression of 4-1BB mRNA was shown in 8 tumor tissues and 6 liver tissues located within 1 to 5 cm away from tumor edge. In PBMCs, 4-1BB mRNA was almost not detected. Percentage of CD4⁺, CD8⁺ and CD3⁺/CD25⁺ T cells, as well as ratio of CD4 to CD8 revealed no difference between groups (P > 0.05, respectively), while a significant lower percentage of CD3⁺ T cell was found in HCC group as compared to healthy control group (P < 0.05). However, 4-1BB molecules were almost not found on the surface of CD4+ and CD8+ T cells in HCC and healthy control group. Double-staining of 4-1BB⁺/CD4⁺ and 4-1BB⁺/CD8⁺ immunofluorescence on tumor infiltrating T cells was detected in 13 liver tissues adjacent to tumor edge (< 1.0 cm) by confocal microscopy.CONCLUSION: Although HCC may escape from immune attack by weak immunogenicity or downregulated expression of MHC-1 molecules on the tumor cell surface, tumor infiltrating T cells can be activated via other costimulatory signal pathways to exert a limited antitumor effect on local microenvironment. The present study also implicates that modulating 4-1BB/4-1BBL costimulatory pathway may be an effective immunotherapy strateg to augment the host response.