| Project/Area Number |
15H04309
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Tumor therapeutics
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| Research Institution | Kyoto University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
馬場 長 京都大学, 医学研究科, 准教授 (60508240)
濱西 潤三 京都大学, 医学研究科, 講師 (80378736)
小西 郁生 京都大学, 医学研究科, 名誉教授 (90192062)
松村 謙臣 京都大学, 医学研究科, 准教授 (20452336)
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| Project Period (FY) |
2015-04-01 – 2018-03-31
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| Project Status |
Completed (Fiscal Year 2017)
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| Budget Amount *help |
¥16,640,000 (Direct Cost: ¥12,800,000、Indirect Cost: ¥3,840,000)
Fiscal Year 2017: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2016: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000)
Fiscal Year 2015: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000)
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| Keywords | 抗VEGF抗体 / 感受性 / 耐性 / 免疫抑制 / 骨髄由来免疫抑制性細胞(MDSCs) / GM-CSF / 抗VEGF抗 / Gr-1 / CD8 / 骨髄由来免疫抑制性細胞 / ピモニダゾール / 低酸素状態 / ＶＥＧＦ抗体 / PD-1抗体 / 耐性遺伝子 / 抗VEGF抗体治療 / Gr-1陽性細胞 / CD8陽性リンパ球 / 薬剤反応性 / 抗ＶＥＧＦ抗体 / 卵巣癌 / 耐性獲得機構 / 発現マイクロアレイ / バイオマーカー |
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| Outline of Final Research Achievements |
The elucidation of the mechanism underlying the development of resistance to anti-VEGF antibodies in ovarian cancer is urgently required. We found that immunosuppression in the tumor microenvironment is associated with resistance to anti-VEGF therapy with the use of preclinical models. Anti-VEGF therapy induced myeloid-derived suppressor cells (MDSCs), which suppressed lymphocyte activity. Anti-VEGF therapy induced tumor hypoxia, which up-regulated the GM-CSF expression in tumor cells and recruited MDSCs into the tumor site. The blockade of GM-CSF signaling improved tumor immunity and enhanced the efficacy of anti-VEGF therapy. Treatments targeting MDSCs induced by VEGF signaling may improve prognosis in patients with high-grade serous ovarian cancer. The development of therapies combining anti-VEGF therapy with drugs targeting tumor immunity is expected.
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