Analysis of inflammatory cytokine IL-18 function in pancreatic cancer cells and the study for therapeutic application using IL-18 inhibitory antibody

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K16443
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 50020:Tumor diagnostics and therapeutics-related
• Research Institution: Shimane University
• Principal Investigator: UCHIDA Yuki 島根大学, 医学部, 医科医員 (60868719)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: インターロイキン18 / 抗体 / 膵臓がん / 5-フルオロウラシル

Outline of Final Research Achievements

To investigate the effect of IL-18 expression on cancer cells, we generated several clones of IL-18 knockout human pancreatic cancer MIA PaCa-2 cells (MIA PaCa-2 / IL-18 KO) by using genome editing technology. These IL-18 KO cells showed no difference in proliferation in culture or in tumorigenicity in nude mice compared to the parent cells, suggesting that IL-18 may have an alternative role. We also prepared MIA PaCa-2 tumor-bearing mice and examined the activation of IL-18 after anti-cancer drug 5-FU treatment, but no clear induction into mice serum was observed. On the other hand, we generated new inhibitory antibodies against the mouse active IL-18 protein, and these results was published an article in an academic journal and was presented in academic conferences. In addition, we clarified the mechanism of active IL-18 production by 5-FU treatment, which is observed in pancreatic cancer cells.

Free Research Field

腫瘍診断および治療学関連

Academic Significance and Societal Importance of the Research Achievements

本研究ではIL-18欠損MIA PaCa-2細胞を作製してその影響を調べたが、自身の増殖や造腫瘍性には影響がないことが示された。がん細胞で発現するIL-18は、細胞自身ではなく周囲のがん微小環境に影響を及ぼしている可能性がある。また抗がん剤5-FUによりヒト膵がん細胞から活性型IL-18が産生されること、そこにはパイロトーシスが関与することを明らかにした。さらに本研究では世界で初めてマウス活性型IL-18に対する阻害抗体を作製した。この抗体はがん研究のみならず、IL-18が関連する炎症性疾患モデルマウスの治療実験に応用できる可能性があり、大きな学術的成果が得られたと考えている。