Antigenic stimulation with cytochrome P450 2J expressed in mouse hepatocellular carcinoma cells regulates host anti-tumour immunity.
Cytochrome P450 2J subfamily (CYP2J) enzymes expressed in mouse hepatocellular carcinoma (HCC) cells were identified as an antigen recognized by specific CD4(+) T cells and the structure of its T cell epitope was determined by proteomics-based exploration. The major histocompatibility complex (MHC) class II binding peptides were isolated from I-A(k)/peptide complex of dendritic cells (DCs) loaded or unloaded with MIH-2 mouse HCC cells. MHC class II-binding peptides found in MIH-2-loaded DCs but not in unloaded DCs were determined by tandem mass spectrometric analysis. The peptide, consisting of amino acid 276-290 (DFIDAFLKEMTKYPE) of mouse CYP2J enzymes, was identified as an antigenic peptide presented in the context of MHC class II. Preventive treatment of mice with CYP2J peptide stimulated interferon (IFN)-gamma production of splenocytes and suppressed the growth of implanted CYP2J-positive MIH-2 cells but not CYP2J-negative murine bladder tumour cells. However, continuous treatment of MIH-2-bearing mice with CYP2J peptide significantly suppressed IFN-gamma production of splenocytes and accelerated the growth of implanted MIH-2 tumours in vivo. Increased frequencies of CD4(+)forkhead box P3 regulatory T cells and CD11b(+)Gr-1(+) myeloid suppressor cells were observed in splenocytes from the continuously immunized mice. These results indicate that antigenecity of CYP2J isoforms expressed in HCC cells activate host anti-tumour immunity at an initial stage of HCC, but suppress host anti-tumour immunity with excessive antigenic stimulation at an advanced stage.
Homma
S
S
Departments of Oncology, Institute of DNA Medicine, Jekei University School of Medicine, Tokyo, Japan. sahya@jikei.ac.jp
Koido
S
S
Sagawa
Y
Y
Suzuki
H
H
Komita
H
H
Nagasaki
E
E
Takahara
A
A
Horiguchi-Yamada
J
J
Tajiri
H
H
Zeldin
D C
DC
Obata
T
T
D000595:Amino Acid Sequence; D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology*; D019496:Cancer Vaccines / Q000494:pharmacology; D006528:Carcinoma, Hepatocellular / Q000276:immunology*; D045744:Cell Line, Tumor; D002846:Chromatography, Affinity; D003577:Cytochrome P-450 Enzyme System / Q000276:immunology / Q000494:pharmacology*; D003713:Dendritic Cells / Q000276:immunology*; D004305:Dose-Response Relationship, Drug; D000949:Histocompatibility Antigens Class II; D007108:Immune Tolerance / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology; D008114:Liver Neoplasms, Experimental / Q000276:immunology*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008969:Molecular Sequence Data; D020033:Protein Isoforms / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013154:Spleen / Q000276:immunology; D053719:Tandem Mass Spectrometry
D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D000949:Histocompatibility Antigens Class II; D020033:Protein Isoforms; D007371:Interferon-gamma; D003577:Cytochrome P-450 Enzyme System