Analysis of regulatory mechanism of NKG2A / HLA-E pathway in gastric cancer

2021 Fiscal Year Final Research Report

• Project/Area Number: 20K16308
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 50010:Tumor biology-related
• Research Institution: Kumamoto University
• 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)
• Project Period (FY): 2020-04-01 – 2022-03-31
• Keywords: 胃癌 / NK細胞 / HLA-E / 可溶性HLA-E

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.

Free Research Field

腫瘍生物学、消化器外科学

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。