| Project/Area Number |
18K19458
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| Research Category |
Grant-in-Aid for Challenging Research (Exploratory)
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| Allocation Type | Multi-year Fund |
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| Review Section |
Medium-sized Section 49:Pathology, infection/immunology, and related fields
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| Research Institution | Sapporo Medical University |
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Principal Investigator |
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| Project Period (FY) |
2018-06-29 – 2021-03-31
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| Project Status |
Completed (Fiscal Year 2020)
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| Budget Amount *help |
¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000)
Fiscal Year 2020: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2019: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
Fiscal Year 2018: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
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| Keywords | がん抗原 / スプライスペプチド / プロテアゾーム / 抗原提示 / がんワクチン / がん免疫療法 / T細胞 / HLA / がん抗原ペプチド / 細胞障害性T細胞 / HLA class I / ネオ抗原 / 抗原提示機構 / 変異抗原 / ネオアンチゲン / 大腸がん / Tumor antigen / Splicing peptide / CTL / Immunotherapy / Neoantigen / Mutation antigen / Antigen processing |
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| Outline of Final Research Achievements |
We could successfully develop the de novo sequencing technology for HLA ligandome analysis, and discovered three spliced peptides derived from wild-type proteins in HCT15 colon cancer cells. Spliced peptide-specific cytotoxic T-cells (CTLs) were induced from peripheral blood lymphocytes of healthy donors by mixed lymphocyte-peptide culture. Two CTL clones were established and analyzed for the cytotoxic potentials, indicating that the novel spliced peptides were highly immunogenic. Then, we analyzed the mechanism of peptide splicing, indicating that the splicing was dependent on the activity of proteasome in the cells. Our data revealed the novel category of neoantigens, which might contribute to the development of a prophylactic cancer vaccine as well as a therapeutic cancer vaccine.
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| Academic Significance and Societal Importance of the Research Achievements |
本研究で最大の学術的意義は、ヒト大腸がん細胞から新規スプライスペプチドを同定し、抗原特異的CTLクローンの樹立に成功した点にある。親タンパクはがん細胞だけでなく、正常組織にも発現しているハウスキーピング分子である。それにも関わらず、スプライスペプチドの高い免疫原性が確認されたことは、この分子のスプライスががん細胞特異的に生じている可能性を示唆する結果であり、遺伝子変異に依存しない新しいネオアンチゲンの産生メカニズムとして大きな細胞生物学的意義がある。また、患者に共通して適応されるネオアンチゲンワクチン創薬に貢献することが期待され、今後がん予防ワクチンの実用化にも道が拓かれる可能性もある。
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