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Antigenic stimulation with cytochrome P450 2J expressed in mouse hepatocellular carcinoma cells regulates host
1Departments of Oncology, Institute of DNA Medicine, Jekei University School of Medicine, Tokyo, Japan. sahya@jikei.ac.jp
Abstract:
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.
Insights
Hepatocellular carcinoma (HCC) antigen, Cytochrome P450 2J (CYP2J), activates anti-tumor immunity initially. However, excessive stimulation suppresses immunity in advanced HCC by increasing regulatory T cells.
Area of Science:
- Immunology
- Oncology
- Biochemistry
Background:
- Hepatocellular carcinoma (HCC) presents unique antigens.
- CD4(+) T cells recognize specific antigens in HCC.
- Cytochrome P450 2J (CYP2J) enzymes are expressed in HCC cells.
Purpose of the Study:
- To identify and characterize T cell epitopes from CYP2J in HCC.
- To investigate the therapeutic potential of CYP2J-derived peptides in HCC.
- To understand the dual role of CYP2J antigenicity in HCC immunity.
Main Methods:
- Proteomics and mass spectrometry to identify MHC class II binding peptides.
- In vivo studies using mouse models of HCC.
- Flow cytometry to analyze immune cell populations (e.g., regulatory T cells).
Main Results:
- A specific CYP2J peptide (amino acid 276-290) was identified as an MHC class II-presented epitope.
- Preventive treatment with the CYP2J peptide stimulated anti-tumor immunity and suppressed tumor growth.
- Continuous treatment led to suppressed immunity and accelerated tumor growth, associated with increased regulatory T cells and myeloid suppressor cells.
Conclusions:
- CYP2J antigenicity can activate host anti-tumor immunity in early-stage HCC.
- Excessive antigenic stimulation of CYP2J suppresses anti-tumor immunity in advanced HCC.
- The findings highlight the complex role of tumor antigens in modulating immune responses during cancer progression.
