Mechanism of immune-evasion associated with epithelial mesenchymal transition in ovarian cancer

• Project/Area Number: 17K11275
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Obstetrics and gynecology
• Research Institution: Department of Clinical Research, National Hospital Organization Kyoto Medical Center (2018-2019); Kyoto University (2017)
• Principal Investigator: Abiko Kaoru 独立行政法人国立病院機構(京都医療センター臨床研究センター), 内分泌代謝高血圧研究部, 研究員 (20508246)
• Co-Investigator(Kenkyū-buntansha): 村上 隆介 京都大学, 医学研究科, 特定病院助教 (40782363) ; 濱西 潤三 京都大学, 医学研究科, 講師 (80378736)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 卵巣癌 / 上皮間葉転換 / 免疫抑制性細胞 / 抗腫瘍免疫 / 免疫逃避 / ケモカイン / MDSC / 免疫治療 / 遊走 / 免疫学

Outline of Final Research Achievements

We focused on transcription factor Snail, which plays a central role in Epithelial-Mesenchymal transition (EMT). In Snail-depleted mouse ovarian cancer, the tumor growth was inhibited. Snail induced the expression of chemokines such as CXCL1 and CXCL2, and increased the infiltration of Myeloid-derived suppressor cells (MDSC) in tumor microenvironment. High concentration of CXCL1/2 was found in ovarian cancer patients' serum. CXCL1/2 was also associated with poor prognosis and high number of MDSCs in the tumor.

Academic Significance and Societal Importance of the Research Achievements

これまで上皮間葉転換（EMT)は癌の進展や転移に関連があることが知られていたが、免疫との関連はよくわかっていなかった。今回、EMTが起こっているときに、SnailによるCXCL1/2の発現を通して、免疫抑制性細胞のMDSCが腫瘍内に浸潤してくることを初めて示し、EMTが免疫抑制と関連していることを示した。また、担癌患者のCXCL1/2の血清中濃度を測定することで、腫瘍内のMDSC数といった免疫状態を推定することが可能であることが示唆され、CXCL1/2の腫瘍免疫バイオマーカーとしての価値も確認された。

Research Products

• [Journal Article] Anti-VEGF therapy resistance in ovarian cancer is caused by GM-CSF-induced myeloid-derived suppressor cell recruitment. (2020)
  • Author(s): Horikawa N, Abiko K, Matsumura N, Baba T, Hamanishi J, Yamaguchi K, Murakami R, Taki M, Ukita M, Hosoe Y, Koshiyama M, Konishi I, Mandai M.
  • Journal Title: Br J Cancer. Volume: 122(1) Issue: 6 Pages: 778-788
  • DOI: 10.1038/s41416-019-0725-x
  • Peer Reviewed / Open Access
• [Journal Article] Snail promotes ovarian cancer progression by recruiting myeloid-derived suppressor cells via CXCR2 ligand upregulation. (2018)
  • Author(s): Taki M, Abiko K, Baba T, Hamanishi J, Yamaguchi K, Murakami R, Yamanoi K, Horikawa N, Hosoe Y, Nakamura E, Sugiyama A, Mandai M, Konishi I, Matsumura N.
  • Journal Title: Nature communications Volume: Apr 27;9(1) Issue: 1 Pages: 1685-1685
  • DOI: 10.1038/s41467-018-03966-7
  • NAID: 120006462510
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Snail promotes ovarian cancer progression by recruiting myeloid-derived suppressor cells via CXCR2 ligand upregulation (2018)
  • Author(s): Mana Taki, Kaoru Abiko, Tsukasa Baba, Junzo Hamanishi, et al.
  • Journal Title: Nature Communications Volume: 印刷中
  • NAID: 120006462510
  • Peer Reviewed / Open Access
• [Presentation] 免疫チェックポイント阻害薬の次へ 骨髄由来免疫抑制性細胞（MDSC）を標的とした卵巣癌新規治療の開発 (2020)
  • Author(s): 安彦 郁
  • Organizer: 第72回日本産科婦人科学会学術講演会
• [Presentation] GM-CSF increases MDSCs infiltration after anti-VEGF therapy in ovarian cancer (2019)
  • Author(s): Kaoru Abiko, Naoki Horikawa, Ryusuke Murakami, Ken Yamaguchi, Junzo Hamanishi, Tsukasa Baba, Masaki Mandai
  • Organizer: SGO Annual Meeting, March 16-19, 2019, Honolulu, HI
  • Int'l Joint Research
• [Presentation] Mechanism of MDSC infiltration in ovarian cancer microenvironment 卵巣癌微小環境におけるMDSC浸潤の機序の解明 (2019)
  • Author(s): Kaoru Abiko, Taki Mana, Naoki Horikawa, Junzo Hamanishi, Ken Yamaguchi, Masaki Mandai
  • Organizer: 第78回癌学会腫瘍別シンポジウム 婦人科がんの発生・病態・治療に関する最新の知見
• [Presentation] GM-CSF increases MDSCs infiltration after anti-VEGF therapy in ovarian cancer (2019)
  • Author(s): Kaoru Abiko, Naoki Horikawa, Ryusuke Murakami, Ken Yamaguchi, Junzo Hamanishi, Tsukasa Baba, Masaki Mandai
  • Organizer: SGO2019
  • Int'l Joint Research
• [Presentation] Snail upregulates CXCL1/2 and induces immune escape through migration of MDSCs in ovarian cancer microenvironment (2018)
  • Author(s): 安彦 郁、滝 真奈、堀川直城、水野 林、村上隆介、濱西潤三、馬場 長、万代昌紀
  • Organizer: 日本癌学会学術総会
• [Presentation] Molecular Target Drugs Biomarker Novel Immunotherapy Targeting MDSCs in Ovarian Cancer (2018)
  • Author(s): Kaoru Abiko
  • Organizer: IGCS2018
  • Int'l Joint Research
• [Presentation] MDSC浸潤を標的とした卵巣癌新規免疫療法の開発 (2017)
  • Author(s): 安彦郁、堀川直城、滝真奈、村上隆介、濱西潤三、馬場長 ほか
  • Organizer: 第76回日本癌学会学術総会