Membrane trafficking system of PD-L1 in gastric cancer cells and its application to immunotherapy

• Project/Area Number: 17K09357
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Nagoya City University
• Principal Investigator: Joh Takashi 名古屋市立大学, 医薬学総合研究院(医学), 名誉教授 (30231369)
• Co-Investigator(Kenkyū-buntansha): 東山 繁樹 愛媛大学, プロテオサイエンスセンター, 教授 (60202272) ; 久保田 英嗣 名古屋市立大学, 医薬学総合研究院(医学), 准教授 (30405188) ; 日吉 裕美 名古屋市立大学, 大学院医学研究科, 助教 (10406530)
• Project Period (FY): 2017-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 胃癌 / Cullin3 / PD-L1/PD-1 / ユビキチン / Cullin-3 / 胃がん / BTB蛋白 / CUL3 / PD-L1 / CUL３

Outline of Final Research Achievements

In this study, we examined the mechanism of PD-L1 intracellular transport regulation by CUL3-BTBP in gastric cancer. Knockdown of CUL3 or BTBP caused changes in PD-L1 expression and subcellular localization; however, the effects differed between the two　molecules. Microarray analysis demonstrated that CUL3 and BTBP do not function together as ubiquitin ligases to control the intracellular transport of PD-L1. We identified a BTBP that controls intracellular transport of PD-L1. Therefore, we are focusing on BTBP to elucidate the mechanism by which it regulates the intracellular transport of PD-L1.

Academic Significance and Societal Importance of the Research Achievements

近年、PD-L1を標的とした免疫チェックポイント阻害剤が開発されが、胃がんへの効果は限定的で改善の余地は大きい。既存のPD-L1抗体薬とは異なる作用機序を持つ薬剤の開発が望まれるが、そのためには、胃がんにおけるPD-L1発現や細胞内輸送制御の機序を解明することが必要である。本研究では、想定していたCUL3-BTBP軸によるPD-L1発現および細胞内輸送制御は確認できなかったが、BTBP単独でPD-L1発現および細胞内輸送制御に関与していることを示唆する知見を得ることができた。本研究の成果は、さらに研究を推進することで、新たな免疫チェックポイント阻害剤の開発につながるものであると考えられる。

Research Products

• [Journal Article] The CUL3-SPOP-DAXX axis is a novel regulator of VEGFR2 expression in vascular endothelial cells (2017)
  • Author(s): Sakaue T, Sakakibara I, Fujisaki A, Uesugi T, Nakashiro K, Hamakawa H, Kubota E, Joh T, Imai Y, Izutani H, Higashiyama S.
  • Journal Title: Sci Rep. Volume: 7 Issue: 1 Pages: 42845-42845
  • DOI: 10.1038/srep42845
  • Peer Reviewed / Open Access
• [Journal Article] Neddylated Cullin 3 is required for vascular endothelial-cadherin-mediated endothelial barrier function. (2017)
  • Author(s): Sakaue T, Fujisaki A, Nakayama H, Maekawa M, Hiyoshi H, Kubota E, Joh T, Izutani H, Higashiyama S.
  • Journal Title: Cancer Sci. Volume: 108 Issue: 2 Pages: 208-215
  • DOI: 10.1111/cas.13133
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Cullin-3 and its adaptor protein ANKFY1 determine the surface level of integrin beta1 in endothelial cells. (2017)
  • Author(s): Maekawa M, Tanigawa K, Sakaue T, Hiyoshi H, Kubota E, Joh T, Watanabe Y, Taguchi T, Higashiyama S
  • Journal Title: Biolology Open Volume: 6 Pages: 1707-1719
  • DOI: 10.1242/bio.029579
  • Peer Reviewed / Open Access