2018 Fiscal Year Final Research Report
Analysis of intra-tumor immune response toward development of autologous gamma-delta T-cell transfer therapy in patients with advanced urothelial carcinoma
| Project/Area Number |
15K10577
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Urology
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| Research Institution | Teikyo University (2017-2018)
The University of Tokyo (2015-2016) |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
久米 春喜 東京大学, 医学部附属病院, 教授 (10272577)
垣見 和宏 東京大学, 医学部附属病院, 特任教授 (80273358)
松下 博和 愛知県がんセンター(研究所), 腫瘍免疫制御TR分野, 分野長 (80597782)
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| Project Period (FY) |
2015-04-01 – 2019-03-31
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| Keywords | 尿路上皮癌 / 腫瘍免疫 / 次世代シーケンサー / CIBERSORT / γδT細胞 / NKG2D |
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| Outline of Final Research Achievements |
Advanced urothelial cancer is notorious for its poor prognosis, and development of novel therapies has long been awaited. We examined the anti-tumor immune response of urothelial cancer in order to develop novel immunotherapies, specifically, gamma-delta T cell therapy as a combination immunotherapy with checkpoint blockades or as a sole treatment for the cases resistant to them. Gamma-delta T cells could be expanded from patients’ PBMC if their percentage exceeded 1.5% in all PBMC and they were not CD27-CD45RAhi exhausted phenotype. Cultured gamma-delta T cells expressed Tim-3 but not PD-1, suggesting that they are less likely suppressed by PD-1/PD-L1 pathways. Therefore, we considered that gamma-delta T cell therapy can be applied even in the cases resistant to checkpoint blockades. The analyses of RNA-seq of surgical specimens revealed that the expression levels of gamma-delta T cell ligands differed according to the extent of CD4+ and CD8+ T cells infiltration into the tumor.
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| Free Research Field |
尿路上皮癌に対する新規治療法の開発
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| Academic Significance and Societal Importance of the Research Achievements |
抗がん剤治療が無効な進行した膀胱がんに対して、免疫チェックポイント阻害剤が承認された。しかし同薬も無効な症例があり、免疫治療の効果を一層高める方法の開発が求められている。本研究では、免疫細胞の一種であるγδT細胞を膀胱がん治療に応用することを目指した。γδT細胞を確実に増殖できる症例の選定、γδT細胞の効果を減弱させる分子の同定・特に抗PD-1抗体薬との併用の可能性、γδT細胞の標的分子の候補を同定した。γδT細胞療法は、免疫チェックポイント阻害剤の効果が期待できない腫瘍に対する対策として、また免疫チェックポイント阻害剤との併用治療での治療効果の増強が期待される。
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