Sarcopenia and immunological tumor microenvironment
| 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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Report
(4 results)
Research Products
(6 results)
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[Journal Article] Conophylline suppresses pancreatic cancer desmoplasia and cancer-promoting cytokines produced by cancer-associated fibroblasts2019
Author(s)
N. Ishii, K. Araki, T. Yokobori, K. Hagiwara, G. Dolgormaa, T. Yamanaka, T. Handa, M. Tsukagoshi, T. Igarashi, A. Watanabe, N. Kubo, N. Harimoto, A. Masamune, K. Umezawa, H. Kuwano, K. Shirabe
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Journal Title
Cancer Science
Volume: 10
Issue: 1
Pages: 334-434
DOI
Related Report
Peer Reviewed / Open Access
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[Presentation] 腫瘍浸潤マクロファージ由来のTNF-αがPD-L1の発現を増強し、膵癌患者における予後不良の原因となる2019
Author(s)
塚本雅代、今井克憲、石本崇胤、菰原義弘, 中川茂樹, 梅崎直紀, 山尾宣暢, 北野雄希, 宮田辰徳, 有馬浩太, 岡部弘尚, 山下洋市, 近本 亮, 石河隆敏, 廣田昌彦, 馬場秀夫
Organizer
第77回日本癌学会学術総会
Related Report
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