Elucidation of the acquisition mechanism of immune escape mechanism of pancreatic cancer using single cell analysis and development of control methods

• Project/Area Number: 20K22818
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Multi-year Fund
• Review Section: 0901:Oncology and related fields
• Research Institution: Kyushu University
• Principal Investigator: TAKESUE Shin 九州大学, 医学研究院, 共同研究員 (30883425)
• Project Period (FY): 2020-09-11 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000); Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 膵癌 / CAF / 膵癌自然発癌モデル / scRNA-seq / 免疫微小環境 / 単一細胞解析 / 免疫逃避機構 / 腫瘍微小環境

Outline of Research at the Start

KPCマウス由来膵癌細胞をC57BL/6マウスに同所移植することで腫瘍免疫を含めた膵癌周囲微小環境を再現する。これにより、腫瘍免疫の観点から、移植早期における癌細胞を排除する段階である「排除相」から、癌細胞が抗原性の高い自己抗原やMHC分子を消失する等により免疫逃避機構を構成し始める「平衡相」、さらには腫瘍免疫抑制細胞を導入し免疫逃避機構を確立する「逃避相」に移行するまで、段階的に再現可能となる。各段階における細胞集団の変化をシングルセル発現解析を行い可視化する。その結果より、腫瘍免疫逃避機構のhubとなる新たな細胞集団を同定し、それらの制御法を確立、膵癌における新規免疫治療薬開発につなげる。

Outline of Final Research Achievements

We transplanted pancreatic cancer cells derived from a spontaneous pancreatic carcinogenesis model into C56BL/6 mice. Pin1, a proline isomerase, was overexpressed in pancreatic cancer cells and CAFs, indicating that targeted therapy against Pin1 can remodel the immunosuppressive microenvironment. Next, we evaluated the immunosuppressive microenvironment by scRNA-seq in human gastric cancer, a gastrointestinal cancer. We found that the expression of immunosuppression-related genes in myeloid cells was higher than in other immunosuppressive cells.

Academic Significance and Societal Importance of the Research Achievements

Pin1分子は膵癌に対して有望な新規治療薬であり、難治性膵癌の治療に活路を見出す可能性が示唆された。また、Pin1は癌関連線維芽細胞にも過剰発現しており、スキルス胃癌などの豊富な間質成分を有する他の癌腫でも有望な標的分子であると考えられた。

Research Products

• [Journal Article] Bone marrow-derived macrophages converted into cancer-associated fibroblast-like cells promote pancreatic cancer progression (2021)
  • Author(s): Iwamoto Chika、Ohuchida Kenoki、Shinkawa Tomohiko、Okuda Sho、Otsubo Yoshiki、Okumura Takashi、Sagara Akiko、Koikawa Kazuhiro、Ando Yohei、Shindo Koji、Ikenaga Naoki、Nakata Kohei、Moriyama Taiki、Miyasaka Yoshihiro、Ohtsuka Takao、Eto Masatoshi、Akashi Koichi、Nakamura Masafumi
  • Journal Title: Cancer Letters Volume: 512 Pages: 15-27
  • DOI: 10.1016/j.canlet.2021.04.013
  • Peer Reviewed / Open Access
• [Presentation] Functions of CD8-positive T cells in gastric non-solid type poorly differentiated adenocarcinoma (2022)
  • Author(s): Chikanori Tsutsumi, Kenoki Ohuchida, Shoichi Nakamura, Sho Okuda, Kyoko Hisano, Yoshiki Otsubo, Koji Shindo, Taiki Moriyama, Yusuke Mizuuchi, Kohei Nakata, Masafumi Nakamura
  • Organizer: INTERNATIONAL GASTRIC CANCER CONGRESS 2022
  • Int'l Joint Research