Identification of anti-tumor effects for semaphorin molecules through regulation of macrophage polarization

2019 Fiscal Year Final Research Report

• Project/Area Number: 17K15722
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Immunology
• Research Institution: Osaka University
• Principal Investigator: Kang Sujin 大阪大学, 免疫学フロンティア研究センター, 寄附研究部門助教 (30644398)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: マクロファージ / セマフォリン / TAM

Outline of Final Research Achievements

Differentiation into inflammatory and suppressive macrophages requires the　activation of appropriate intracellular metabolism via mTOR signaling, but the detailed mechanism has not been elucidated. In the present study, the authors revealed that the signal of mTORーSema6Dー PPARγ is essential for differentiation into inhibitory macrophages.　Inhibition of mTOR or Sema6D gene deficiency reduced PPARγ expression and reduced fatty acid uptake and β-oxidation. As a result, differentiation into inhibitory macrophages was inhibited. Furthermore, the interaction between c-Abl, a Src family tyrosine kinase, was required for the expression of PPARγ. Furthermore, Sema6D tried to differentiate into tumor macrophages (TAM). From the above results, it was revealed that the retrograde signal of Sema6D couples immunity and metabolism via PPARγ and promotes differentiation into inhibitory macrophages.

Free Research Field

免疫学

Academic Significance and Societal Importance of the Research Achievements

Sema6D の機能を阻害する抗Sema6D 抗体(agonist, antagonist)を用いた肥満に対する治療応用が期待される。同時に、マクロファージおよび脂肪細胞におけるSema6D の下流シグナルを標的とした天然化合物ライブラリーによるスクリーニングを行い、新たな分子標的薬を開発への展開が期待される。