Analysis of regulatory mechanism of NKG2A / HLA-E pathway in gastric cancer
| Project/Area Number |
20K16308
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| Research Category |
Grant-in-Aid for Early-Career Scientists
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| Allocation Type | Multi-year Fund |
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| Review Section |
Basic Section 50010:Tumor biology-related
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| Research Institution | Kumamoto University |
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Principal Investigator |
Yamashita Kohei 熊本大学, 大学院生命科学研究部(医), 特定研究員 (00867202)
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| Project Period (FY) |
2020-04-01 – 2022-03-31
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| Project Status |
Completed (Fiscal Year 2021)
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| Budget Amount *help |
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2021: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
Fiscal Year 2020: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
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| Keywords | 胃癌 / NK細胞 / HLA-E / 可溶性HLA-E / NKG2 / Monalizumab / 免疫チェックポイント分子 / NKG2A |
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| Outline of Research at the Start |
NKG2A/HLA-E経路は、NK細胞の活性化を制御する免疫チェックポイント機構で、この経路を標的としたanti-NKG2A抗体(Monalizumab)の前臨床段階での抗腫瘍効果が頭頸部癌で報告された。本研究は、新規免疫チェックポイント機構であるNKG2A/HLA-Eに注目し、胃癌での抗腫瘍免疫応答におけるNK細胞活性化の意義を検討する。また、NKG2A/HLA-Eの発現制御に関わる分子メカニズムを明らかにし、NKG2A/HLA-E阻害剤の治療効果予測のバイオマーカーの同定やPD-1/PD-L1阻害剤及び分子標的治療薬との併用療法の有用性を検討する。
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| Outline of Final Research Achievements |
The NKG2A / HLA-E pathway of the novel immune checkpoint machinery has been reported to be involved in cancer immune escape. Inhibition of this pathway can promote reactivation of NK cells and T cells and exhibits antitumor effects, which is considered a promising immunotherapeutic target in various types of cancer.
In this study, it was demonstrated that high expression of HLA-E and low invasion of NK cells in local tumor site had a poor prognosis in patients with gastric cancer. Moreover, it was also clarified the regulation mechanism of HLA-E, in which HLA-E expression in gastric cancer cell was upregulated by IFNγ stimulation and then cleaved from the cell surface, results in the production of soluble HLA-E. Finally, it was revealed that the soluble HLA-E concentration in the blood of gastric cancer patients increases as the gastric cancer stage progresses.
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| Academic Significance and Societal Importance of the Research Achievements |
進行胃がんは依然として予後不良であり、新たな治療標的やバイオマーカーの創出が急務である。本研究により、胃がんのHLA-E発現及びNK細胞浸潤のバイオマーカーとしての意義が明らかとなり、NKG2A/HLA-E を治療標的とした創薬の展望が開けた。また、胃がん細胞のHLA-E発現がダイナミックに変化する制御機構が明らかとなり、その結果生成される可溶性HLA-Eを血液検査での低侵襲なリキッドバイオプシーとして利用することで、がんの早期発見、がん治療の効果の評価、がん再発の早期発見につながる可能性が示唆された。
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Report
(3 results)
Research Products
(8 results)
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[Presentation] The clinicopathological significance of HLA-E and NK expression in gastric cancer2021
Author(s)
Takeshi Morinaga, Masaaki Iwatsuki, Kohei Yamashita, Taishi Yamane, Tasuku Toihata, Kenichi Nakamura, Yoshifumi Baba, Shiro Iwagami, Yuji Miyamoto, Naoya Yoshida, Hideo Baba
Organizer
第76回日本消化器外科学会総会
Related Report
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[Presentation] The clinicopathological significance of HLA-E expression in advanced gastric cancer2020
Author(s)
Takeshi Morinaga, Masaaki Iwatsuki, Kohei Yamashita, Taishi Yamane, Tasuku Toihata, Kenichi Nakamura, Yoshifumi Baba, Shiro Iwagami, Yuji Miyamoto, Naoya Yoshida, Hideo Baba
Organizer
第79回日本癌学会学術総会
Related Report
