| Project/Area Number |
12557109
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 展開研究 |
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| Research Field |
Digestive surgery
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| Research Institution | Keio University |
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Principal Investigator |
KAWAKAMI Yutaka Keio University, School of Medicine, Professor, 医学部, 教授 (50161287)
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| Co-Investigator(Kenkyū-buntansha) |
SAKURAI Toshiharu Keio University, School of Medicine, Instructor, 医学部, 助手 (20101933)
SUZUKI Yuriko Keio University, School of Medicine, Instructor, 医学部, 助手 (40255435)
FUJITA Tomonobu Keio University, School of Medicine, Instructor, 医学部, 助手 (20199334)
IWAI Takehisa Tokyo Medical and Dental University Faculty of Medicine, Professor, 医学部, 教授 (90111591)
KITAJIMA Masaki Keio University, School of Medicine, Professor, 医学部, 教授 (90112672)
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| Project Period (FY) |
2000 – 2001
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| Project Status |
Completed (Fiscal Year 2001)
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| Budget Amount *help |
¥13,200,000 (Direct Cost: ¥13,200,000)
Fiscal Year 2001: ¥5,000,000 (Direct Cost: ¥5,000,000)
Fiscal Year 2000: ¥8,200,000 (Direct Cost: ¥8,200,000)
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| Keywords | Microsatellite instability / Colorectal cancer / Tumor antigen / CDX2 / Frameshift / Antibody / T lymphocyte / Immunotherapy / フレイムシフト / cDNAクローニング / SEREX法 / 腫瘍特異的変異ペプチド / 遺伝子診断 |
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| Research Abstract |
Microsatellite instability positive colorectal cancers (MSI+CRC) caused by malfunction of DNA mismatch repair has unique characteristics including good prognosis with T-cell infiltrates, suggesting immune responses against tumor specific peptides generated by frameshift mutations. In this study, we have attempted to identify tumor antigens involved in MSI+CRC. We first applied SEREX to identify tumor antigens that induced IgG in MSI+CRC patients, then, immunogenicity of the antigens was evaluated by detecting IgG among sera from various cancer patients and healthy individuals. 150 antigens including 75 antigens for that IgG were detected only in MSI+CRC patients, were identified. The frameshift mutation in the repetitive sequence in the isolated CDX2 antigen was found in the tumor tissue of the patient with antrCDX2 antibody. Using recombinant frameshift CDX2 proteins, the antibody was found to recognize the C-terminal unique peptide caused by the frameshift mutation. This antibody was disappeared 7 years after the curative resection, suggesting that the immune responses may be useful as tumor markers. Although in vitro induction of T-cells specific for the mutated CDX2 was attempted, specific T cells were not induced possibly because of the use of lymphocytes from the 7 year disease free patient. We have also evaluated whether IgG were detected against possible frameshift peptides from the known MSI target genes. However, no IgG was detected against any recombinant peptides tested. In summary, we demonstrated for the first time that tumor specific immune response against the frameshift peptides caused by MSI could be induced in MSI+CRC patients. These tumor specific mutated peptides may be useful for the development of diagnostic and therapeutic methods for patients with MSI+ CRC. SEREX using autologous tumors and analysis of immune responses against the frameshift peptides using patient's T-cells should be performed in the further study.
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