The involvement of Neutrophil extracellular traps (NETs) in the development of peritoneal metastasis in terms of the interaction with host immunity

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K09131
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 55020:Digestive surgery-related
• Research Institution: Jichi Medical University
• Principal Investigator: Miyato Hiedeyo 自治医科大学, 医学部, 講師 (90813163)
• Co-Investigator(Kenkyū-buntansha): 北山 丈二 自治医科大学, 医学部, 教授 (20251308) ; 細谷 好則 自治医科大学, 医学部, 教授 (30275698) ; 大澤 英之 自治医科大学, 医学部, 講師 (60458271) ; 井上 賢之 自治医科大学, 医学部, 講師 (80375279)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: 好中球細胞外トラップ / 腹膜播種 / 免疫 / エクソソーム

Outline of Final Research Achievements

In this study, we investigated the effects of neutrophil extracellular traps (NETs) on migration of immune cells and cytotoxic effect of anti-cancer drugs. NETs induced peripheral blood monocyte to differenciate into M1 macrophage. On the other hand, NETs degradated chemokines such as CXCL10 or CXCL11 which act as chemoattractant of lymphocytes, dependent on neutrophil elastase or serine protease, and inhibited lymphocytes migration toword these chemokines. These results indicated that NETs might induce immunosuppression inhibitting intratumoral invasion of lymphocytes and attenuate anit-tumor immunity. NETs trapped anti-cancer drugs such as doxorubicin or paclitaxel, inhibitted cytotoxic effect of these drugs and reduced apoptosis of cancer cells. These effects might be collectively involved in the mechanism of tumor promoting effects of NETs.

Free Research Field

腫瘍微小環境

Academic Significance and Societal Importance of the Research Achievements

NETsは腫瘍微小環境において、リンパ球の腫瘍内への浸潤を阻害し抗腫瘍免疫を抑制したり、腫瘍内への抗がん剤の浸透を阻害することにより、複合的に腫瘍の進展を促進する作用を有する可能性が示唆された。以上の結果から、DNAseや好中球エラスターゼ阻害剤、セリンプロテアーゼ阻害剤などNETsの作用を阻害する薬剤を使用することにより、リンパ球の腫瘍内への浸潤や抗がん剤の腫瘍内への浸透性を高める新たな治療法の開発の可能性が示唆された。