| Project/Area Number |
19K16699
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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 49070:Immunology-related
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| Research Institution | Tokyo Medical University |
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Principal Investigator |
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| Project Period (FY) |
2019-04-01 – 2022-03-31
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| Project Status |
Completed (Fiscal Year 2021)
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| Budget Amount *help |
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2021: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
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| Keywords | 肺癌 / SMAD / STAT / 樹状細胞 / Tリンパ球 / 形質転換増殖因子β（TGF-β） / 炎症 / 信号伝達 / 抗腫瘍免疫 / Lung cancer / Anti-tumor immunity / Dendritic cell / T cell / TGF-beta / SMADs / STATs / lung cancer / lung mucosal immunity |
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| Outline of Research at the Start |
SMAD-mediated TGF-β signaling and JAK/STATs play crucial roles in lung carcinogenesis. Unrevealed SMAD-STAT signaling networks in anti-lung cancer immunity might induce poor prognosis and drug resistance. To elucidate the roles of SMAD-STAT signaling networks in anti-lung cancer immunity, I will investigate: <1> Roles of SMADs in DCs and T cells in lung mucosal immune homeostasis and <2> in lung cancer, <3> Effects of SMAD deficiency on STAT signaling in DCs and T cells in lung cancer, <4> Mechanisms how SMAD-STAT signaling networks regulate DCs and T cells in anti-lung cancer immunity.
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| Outline of Final Research Achievements |
Transforming growth factor (TGF)-β and various inflammatory cytokines enhance cancer progression, while suppressing anti-tumor immunity in tumor microenvironment including lung cancer, which is the leading cause of death in Japan. This research has focused on the networking of the intracellular signaling molecules of these cytokines: SMADs for TGF-β and STATs for inflammatory cytokines in the regulation of anti-lung cancer immunity and homeostasis of the adoptive immune system in the lungs.
I have found that STATs and SMADs cooperate to regulate the differentiation of conventional and plasmacytoid dendritic cell subsets. Inhibition of a certain SMAD pathway in dendritic cells was found to be efficiently enhance anti-lung cancer immunity. I have found that the classical SMAD pathways and non-classical SMAD pathways exert distinct functions in T cell-mediated anti-lung cancer immunity.
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| Academic Significance and Societal Importance of the Research Achievements |
本邦において死亡原因第一位の癌である肺癌の治療は、遺伝子変異に対する分子標的薬や免疫チェックポイント阻害薬の登場によって大きく進歩したが、治療抵抗性の獲得、再発、副作用の問題解決が望まれている。
一方、免疫チェックポイント阻害薬の基礎研究以前から長年にわたり癌に対するTGF-β阻害薬の臨床治験が行われてきたが、未だ臨床に用いる段階に達していない。
本研究は、これら懸案を解決する基礎となり得る。
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