Regulatory mechanisms of immune checkpoint PD-L1 via the Arf6 pathway in progressive cancer

2021 Fiscal Year Final Research Report

• Project/Area Number: 17K08614
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: General medical chemistry
• Research Institution: Hokkaido University
• Principal Investigator: Hashimoto Ari 北海道大学, 医学研究院, 助教 (60390803)
• Project Period (FY): 2017-04-01 – 2022-03-31
• Keywords: Arf6 / PD-L1 / 免疫チェクポイント / 免疫回避 / 癌免疫

Outline of Final Research Achievements

We previously showed that the small GTPase Arf6 and its downstream effector AMAP1 constitute the core signaling machinery that drives cancer malignancy and therapeutic resistance in breast and renal cancers. In this project, we showed that mutations in KRAS/TP53, the major driver oncogenes of pancreatic cancer, cooperatively cause the overexpression of Arf6 and AMAP1 proteins and activation of the Arf6-AMAP1 pathway to promote PDAC invasion, metastasis, fibrosis, and immune evasion. Mechanistically, the Arf6-AMAP1 pathway promoted recycling of the immune checkpoint molecule PD-L1 to the cell membrane surface. We also found that the epigenetic factor EZH2 is involved in the regulation of Arf6 and PD-L1 expression, and identified candidate molecules for its regulation. Moreover, we demonstrated that inhibition of the Arf6-AMAP1 pathway in cancer cells results in therapeutic synergy with an anti-PD-1 antibody, and is hence a novel method for improving the efficacy of anti-PD-1 therapies.

Free Research Field

分子細胞生物学

Academic Significance and Societal Importance of the Research Achievements

本研究により、膵癌のドライバー変異がArf6-AMAP1経路を高発現活性化することにより、膵癌の悪性度進展を促進し、悪性予後因子となる重要な知見を得た。さらに、エピジェネティック因子EZH2はArf6経路因子及びPD-L1の遺伝子発現に関わること、Arf6-AMAP1経路はPD-L1の細胞内動態制御にも関わり，免疫回避を駆動していることを見出した。実際、Arf6-AMAP1経路阻害は免疫チェックポイント阻害療法に対する抵抗性を改善し、奏功性を相乗的に高めることを実証した。本研究成果により、Arf6-AMAP1の高発現は膵癌の適用バイオマーカーとして有効であり、新規治療戦略の創出が期待出来る。