| Project/Area Number |
18K07922
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Review Section |
Basic Section 53010:Gastroenterology-related
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| Research Institution | Kindai University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
西田 直生志 近畿大学, 医学部, 准教授 (60281755)
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| Project Period (FY) |
2018-04-01 – 2021-03-31
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| Project Status |
Completed (Fiscal Year 2020)
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| Budget Amount *help |
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2020: ¥520,000 (Direct Cost: ¥400,000、Indirect Cost: ¥120,000)
Fiscal Year 2019: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
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| Keywords | 肝細胞癌 / 微小免疫環境 / 免疫チェックポイント阻害剤 / チロシンキナーゼ阻害剤 / PI3K-Akt経路 / β-catenin経路 / b-カテニン経路 / 腫瘍免疫 / 遺伝子変異 / PI3K / βカテニン / 免疫チェックポイント / PD-L1 / 免疫微小環境 / 免疫 |
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| Outline of Final Research Achievements |
To know how the effectively the response to immune checkpoint inhibitors (ICIs) can be enhanced, we explored the immunological and molecular characteristics of HCCs. Programmed cell death ligand 1 (PD-L1)-positive HCCs frequently showed inflamed phenotype; a subset of HCCs carried mutation in PI3K-Akt pathway. In HCCs with infiltration of TILs, CD8+ cells expressed multiple co-inhibitory receptors, suggesting T-cell exhaustion. On the other hands, PD-L1-negative HCCs showed activating mutations in β-catenin, such tumor exhibited non-inflamed phenotype. Through the analysis of the HCC patients treated with anti-PD-1 therapy, the combined of Wnt/β-catenin activation, PD-L1 expression, and degree of CD8+ TILs in HCC are revealed to be the predicting factor for the response to ICI. Tyrosine kinase inhibitor involving PI3K/Akt pathway, in combination with ICI, might effective in HCC with mutation in PI3K-Akt. Role of β-catenin inhibitor on immune cold HCC should also be explored.
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| Academic Significance and Societal Importance of the Research Achievements |
PD-L1陽性肝癌は免疫細胞浸潤(TIL)が多く、しかしTILには複数の抑制型受容体が発現しており、PI3K-Akt変異例が比較的多い。従って、PI3K-Akt活性に介在するチロシンキナーゼ阻害剤が併用に有利である可能性がある。PD-L1陰性肝癌はTILに乏しく β-カテニン経路活性型変異を持つ。β-カテニン阻害剤の腫瘍免疫への影響を検討する余地がある。PD-L1発現肝癌は、CK-19やSALL4陽性例が多いが、従来治療に難治であり、ICIとPI3K-Ak阻害剤併用に期待が持たれる。TILに複数の抑制型受容体が発現していることより、2種の抑制型受容体に対する複合免疫療法にも期待される。
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