Development of personalized treatment by stratification targeting the microenvironment of ovarian cancer

• Project/Area Number: 18K16769
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 56040:Obstetrics and gynecology-related
• Research Institution: Research Institute, Shiga Medical Center (2019); Kyoto University (2018)
• Principal Investigator: Murakami Ryusuke 滋賀県立総合病院(研究所), その他部局等, 医長 (40782363)
• Project Period (FY): 2018-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2019: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2018: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 卵巣癌 / 腫瘍微小環境 / トランスレーショナルリサーチ / CD276

Outline of Final Research Achievements

We reported that histopathological classification based on tumor microenvironment reflecting the gene expression profile of high-grade serous ovarian cancer was associated with prognosis and treatment sensitivity. Analysis of the gene expression profiles of the Immune Reactive type with the best prognosis and the Mesenchymal Transition with the poorest prognosis revealed that the immune checkpoint molecule CD276 is highly expressed in tumors and stroma with poor prognosis. We verified that CD276 not only suppresses direct T cell activity as an immunosuppressive factor but also induces M2 macrophages, which are immunosuppressive cells, through the expression of CCL2 in ovarian cancer innate immunized mice. I devise treatments that control the immunosuppressive pathways.

Academic Significance and Societal Importance of the Research Achievements

予後不良な卵巣高異型度漿液性癌のMesenchymal Transitionにおいて、免疫抑制が腫瘍微小環境で高発現しているCD276により、直接的な活性化Tリンパ球への抑制効果と、間接的に免疫抑制系細胞であるM2マクロファージを誘導することで、免疫抑制環境をより強くさせていることを発見した。本研究で、難治性な卵巣癌に対して複数の免疫抑制経路を遮断する治療がより有効な治療戦略であることが示唆された。

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] The mesenchymal transition subtype more responsive to dose dense taxane chemotherapy combined with carboplatin than to conventional taxane and carboplatin chemotherapy in high grade serous ovarian carcinoma: A survey of Japanese Gynecologic Oncology Group study (JGOG3016A1). (2019)
  • Author(s): Ryusuke Murakami
  • Journal Title: Gynecologic Oncology Volume: May;153(2) Issue: 2 Pages: 312-319
  • DOI: 10.1016/j.ygyno.2019.02.010
  • Peer Reviewed
• [Journal Article] Acquisition of a side population fraction augments malignant phenotype in ovarian cancer. (2019)
  • Author(s): Yamanoi K, Baba T, Abiko K, Hamanishi J, Yamaguchi K, Murakami R, Taki M, Hosoe Y, Murphy SK, Konishi I, Mandai M, Matsumura N.
  • Journal Title: Sci Rep. Volume: 9(1) Issue: 1 Pages: 14215-14215
  • DOI: 10.1038/s41598-019-50794-w
  • NAID: 120006822513
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The efficacy of secondary cytoreductive surgery for recurrent ovarian, tubal, or peritoneal cancer in Tian-model low-risk patients. (2019)
  • Author(s): So M, Miyamoto T, Murakami R, Abiko K, Hamanishi J, Baba T, Mandai M.
  • Journal Title: J Gynecol Oncol. Volume: Nov;30(6) Issue: 6
  • DOI: 10.3802/jgo.2019.30.e100
  • NAID: 120006894002
  • Peer Reviewed
• [Journal Article] VISTA expressed in tumour cells regulates T cell function (2018)
  • Author(s): Mulati Kumuluzi、Hamanishi Junzo、Matsumura Noriomi、Chamoto Kenji、Mise Nathan、Abiko Kaoru、Baba Tsukasa、Yamaguchi Ken、Horikawa Naoki、Murakami Ryusuke、Taki Mana、Budiman Kharma、Zeng Xiang、Hosoe Yuko、Azuma Miyuki、Konishi Ikuo、Mandai Masaki
  • Journal Title: British Journal of Cancer Volume: 120 Issue: 1 Pages: 115-127
  • DOI: 10.1038/s41416-018-0313-5
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] 卵巣高異型度漿液性癌の細病理分類Mesenchymal Transition typeに対するBevacizumab併用化学療法の有用性について (2019)
  • Author(s): 村上 隆介
  • Organizer: 第1回婦人科がんゲノム研究会
• [Presentation] CD276 expression on ovarian cancer induces infiltration of myeloid derived suppressor cells (2019)
  • Author(s): Taito Miyamoto, Ryusuke Murakami,
  • Organizer: 第78回日本癌学会学術総会