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Expression of chondroitin‐glucuronate C5‐epimerase and cellular immune responses in patients with hepatocellular carcinoma
Author(s) -
Mizukoshi Eishiro,
Fushimi Kazumi,
Arai Kuniaki,
Yamashita Tatsuya,
Honda Masao,
Kaneko Shuichi
Publication year - 2012
Publication title -
liver international
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.873
H-Index - 110
eISSN - 1478-3231
pISSN - 1478-3223
DOI - 10.1111/j.1478-3231.2012.02853.x
Subject(s) - glucuronate , elispot , chondroitin , cytotoxic t cell , immunogenicity , antigen , immunotherapy , peripheral blood mononuclear cell , chemistry , antigenicity , hepatocellular carcinoma , microbiology and biotechnology , immune system , cancer research , biology , immunology , biochemistry , glycosaminoglycan , cd8 , in vitro
Background & Aims Chondroitin‐glucuronate C5‐epimerase is an enzyme that converts D‐glucuronic acid to L‐iduronic acid residues in dermatan sulphate biosynthesis. It is also identified to be a tumour‐associated antigen recognized by cytotoxic T cells ( CTL s) and its enhanced expression in many cancers has been reported. In the present study, we investigated the usefulness of this molecule as an immunotherapeutic target in hepatocellular carcinoma ( HCC ). Methods The expression of chondroitin‐glucuronate C5‐epimerase in hepatoma cell lines and HCC tissues was confirmed by immunofluorescence and immunohistochemical analysis. CTL responses were investigated by several immunological techniques using peripheral blood mononuclear cells ( PBMC s) or tumour‐infiltrating lymphocytes. To determine the safety of immunotherapy using chondroitin‐glucuronate C5‐epimerase‐derived peptide, 12 patients with HCC were administered s.c. vaccinations of the peptides and analysed. Results Chondroitin‐glucuronate C5‐epimerase was expressed in HCC cell lines and human tissues including alpha‐foetoprotein ( AFP )‐negative individuals. Chondroitin‐glucuronate C5‐epimerase‐specific CTL s could be generated by stimulating PBMC s of HCC patients with peptides and they showed cytotoxicity against HCC cells expressing the protein. The frequency of CTL precursors investigated by enzyme‐linked immunospot ( ELISPOT ) assay was 0–34 cells/3 × 10 5 PBMC s and the infiltration of interferon‐gamma‐producing CTL s into the tumour site was confirmed. In the vaccination study, no severe adverse events were observed and the peptide‐specific CTL s were induced in 4 of 12 patients tested. Conclusions Chondroitin‐glucuronate C5‐epimerase is a potential candidate for tumour antigen with immunogenicity and the peptides derived from this antigen could be useful in HCC immunotherapy.