| Project/Area Number |
17K10704
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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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| Research Field |
Digestive surgery
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| Research Institution | Kumamoto University |
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Principal Investigator |
Imai Katsunori 熊本大学, 大学院生命科学研究部(医), 助教 (60555746)
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| Co-Investigator(Kenkyū-buntansha) |
中川 茂樹 熊本大学, 病院, 非常勤診療医師 (10594872)
東 孝暁 熊本大学, 病院, 医員 (70594878)
林 洋光 熊本大学, 病院, 助教 (80625773)
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| Project Period (FY) |
2017-04-01 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
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| Keywords | 腫瘍免疫学 / 免疫チェックポイント / 膵癌 / マクロファージ / 腫瘍微小環境 / PD-1 / PD-L1 / 腫瘍免疫 / 腫瘍浸潤マクロファージ / TNF-α / サルコペニア / 免疫学的癌微小環境 |
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| Outline of Final Research Achievements |
We investigated the clinical significance and regulatory mechanism of PD-L1 expression in pancreatic ductal adenocarcinoma (PDAC) cells. Among the various cytokines tested, tumor necrosis factor (TNF)-α upregulated PD- L1 expression in PDAC cells through NF-κB signaling. The induction of PD-L1 expression was also caused by co-culture with activated macrophages, and the upregulation was inhibited by neutralization with anti- TNF-α antibody after co-culture with activated macrophages. PD-L1 expression in PDAC cells was positively correlated with macrophage infiltration in tumor stroma of human PDAC tissues. In addition, survival analysis revealed that high PD-L1 expression was significantly associated with poor prognosis in 235 PDAC patients and especially in patients harboring high CD8-positive T-cell infiltration. These findings indicate that tumor- infiltrating macrophage-derived TNF-α could be a potential therapeutic target for PDAC.
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| Academic Significance and Societal Importance of the Research Achievements |
免疫チェックポイント阻害剤の登場をうけ、抗腫瘍免疫療法は目覚ましい発展を遂げた。しかし治療効果を予測するバイオマーカーは確立しておらず、免疫学的な腫瘍微小環境の機序解明は急務である。
今回我々は膵癌において、免疫チェックポイント分子であるPD-L1の発現が予後に相関し、PD-L1の発現を調節する因子として腫瘍浸潤マクロファージが分泌するTNF-αを同定した。さらに、TNF-αがPD-L1の発現を制御するメカニズムとしてNF-κBの関与を証明し、新たな膵癌治療における治療ターゲットとなる可能性を示した。
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