Sarcopenia and immunological tumor microenvironment

2019 Fiscal Year Final Research Report

• Project/Area Number: 17K10704
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Digestive surgery
• Research Institution: Kumamoto University
• Principal Investigator: Imai Katsunori 熊本大学, 大学院生命科学研究部(医), 助教 (60555746)
• 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)
• Project Period (FY): 2017-04-01 – 2020-03-31
• 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

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.

Free Research Field

消化器外科学、腫瘍免疫学

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。