Avoidance of milk fat globule-epidermal growth factor-8 (MFG-E8) tumor immunity via regulatory B cells and application of mechanism for colon cancer therapy

2020 Fiscal Year Final Research Report

• Project/Area Number: 17K09383
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Shimane University
• Principal Investigator: kawashima Kousaku 島根大学, 学術研究院医学・看護学系, 講師 (10609267)
• Co-Investigator(Kenkyū-buntansha): 石原 俊治 島根大学, 学術研究院医学・看護学系, 教授 (80263531)
• Project Period (FY): 2017-04-01 – 2021-03-31
• Keywords: 腫瘍免疫 / 腸管免疫 / 制御性B細胞 / MFG-E8

Outline of Final Research Achievements

We have reported that milk fat globule-epidermal growth factor-8 (MFG-E8) promotes tumor growth and has a high level of expression in human colon cancer cells. Furthermore, regulatory B cells (Bregs) dysfunction associated with inflammatory bowel disease was found to lead to inflammation exacerbation. However, no mechanism for avoiding MFG-E8 tumor immunity via Bregs has been elucidated. In this study, Bregs number in MFG-E8 knockout (KO) mice was decreased, while CpG DNA-induced IL-10 production was significantly reduced in B cells obtained from those mice. These results suggest an important role of MFG-E8 in Bregs development and differentiation. Unfortunately, MFG-E8 KO mice showed unfavorable reproduction, and experiments focused on tumor incidence and inhibition with colitis-associated cancer model mice did not achieve favorable results. Accelerated Bregs function induced by MFG-E8 may impact development and promotion of colon cancer by inhibiting host tumor immunity.

Free Research Field

消化器内科学、炎症性腸疾患

Academic Significance and Societal Importance of the Research Achievements

今回のMFG-E8 ノックアウト（KO）マウスを用いた研究では、MFG-E8が制御性B細胞（Breg）の発生や分化に重要な役割を果たしていることが明らかとなった。炎症性大腸癌モデルにおける大腸発癌と癌進展抑制に関しては期待した成果は上げることは出来なかったが、MFG-E8によるBregの活性化や機能促進は宿主の腫瘍免疫抑制を介して、大腸癌の発生や進展に影響する可能性があると考えられた。今後、腫瘍に対する免疫療法の新規開発につながる可能性があると思われた。