Neutrophil extracellular trap and immune response in gastrointestinal tumor

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K17629
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 55020:Digestive surgery-related
• Research Institution: Jichi Medical University
• Principal Investigator: Sadatomo Ai 自治医科大学, 医学部, 助教 (40528585)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: 好中球細胞外トラップ / マクロファージ / T細胞 / ケモタキシス / CXCL-11 / 細胞運動 / 免疫チェックポイント分子

Outline of Final Research Achievements

NETs produced by stimulating peripheral blood neutrophils with LPS inhibited the differentiation of monocytes into M2 macrophages and restored the proliferation of T cells stimulated with anti-CD3 mAb. On the other hand, NETs strongly suppressed the chemotaxis of activated T cells to CXCL-11 probably through the degradation of chemokines. The density of NETs in human colon cancer tissues was inversely correlated with the density of CD3(+)CD8(+) T cells, suggesting NETs inhibits the infiltration of T cells in tumor tissue. These facts suggest that NETs in solid tumors have both cancer-promoting and inhibitory effects. However, given that the response to immune checkpoint inhibition therapy is dependent on the accumulation of cytotoxic T cells in tumor stroma, NETs may be negatively associated with patient outcome. Quantification of NETs in resected solid tumor specimens might be a biomarker to predict the sensitivity to immunotherapy.

Free Research Field

消化器外科学

Academic Significance and Societal Importance of the Research Achievements

がんの進展に対する好中球の役割とその機序は十分に解明されていない。本研究にて、活性化好中球由来のNETsがマクロファージの分化を制御すること、活性化Tリンパ球の浸潤を抑制することが新たに判明した。また、ヒト大腸癌切除標本の免疫染色にて、NETsの量がCD8(+) T細胞の浸潤度と逆相関することから、NETsの定量が免疫チェックポイント阻害療法の感受性と相関する事実が解り、臨床応用への道が開かれたという点で社会的意義も大きいと思われる。