| Project/Area Number |
18K16691
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| Research Category |
Grant-in-Aid for Early-Career Scientists
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| Allocation Type | Multi-year Fund |
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| Review Section |
Basic Section 56030:Urology-related
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| Research Institution | Kansai Medical University (2019-2021)
Kyoto University (2018) |
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Principal Investigator |
SAITO Ryoichi 関西医科大学, 医学部, 講師 (30792270)
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| Project Period (FY) |
2018-04-01 – 2022-03-31
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| Project Status |
Completed (Fiscal Year 2021)
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| Budget Amount *help |
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2020: ¥390,000 (Direct Cost: ¥300,000、Indirect Cost: ¥90,000)
Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2018: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
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| Keywords | 膀胱癌 / 尿路上皮癌 / マウス / PD-L1 / 免疫療法 / 腫瘍免疫 / 化合物スクリーニング / 癌免疫療法 / 同系移植モデル |
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| Outline of Final Research Achievements |
For years, the gold standard treatment for metastatic bladder cancer has been CDDP-based chemotherapy. Since several years ago, immune-checkpoint inhibition (ICI) has been shown to be effective in the 2nd line setting post induction chemotherapy. The efficacy of ICI, however, is unfortunately limited up to 30%. We tried to explore new treatment targets that increase the efficacy of ICI in metastatic bladder cancer in combination. One kinase inhibitor and a couple of new agents downregulated the expression of PD-L1 in mouse bladder cancer cells. These agents seemed to suppress the growth of mouse bladder cancer tumor in combination with ICI, but not statistically significant. Genetic analysis of TCGA data showed that PD-L1 high cases had enriched expression of another immune checkpoints such as LAG3 and TIGIT. It might be more important to suppress these signals when treating with PD-1 blockade for metastatic urothelial cancer.
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| Academic Significance and Societal Importance of the Research Achievements |
PD-1経路に着目した免疫チェックポイント阻害剤（ICI)は様々な癌腫の治療成績を向上させたが、奏効する症例は膀胱癌を含め概ね30%程度に過ぎない。そのため、ICIの治療効果をどのように増強するかが重要であり、新規免疫チェックポイント分子を標的とした治療開発が進んでいる。本研究ではPD-L1分子の発現制御によるPD1阻害の増強を目指したが、有意な上乗せ効果は認めなかった。遺伝学的解析からは、LAG3やTIGITなど別系統の免疫チェックポイント分子の阻害と組み合わせるほうがPD1経路阻害効果を増強可能かもしれない。今後は新規チェックポイント阻害剤とPD1阻害剤の併用効果を検討していく予定である。
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