Effects of neutrophil extracellular traps (NETs) on response to cancer immunotherapy.

2022 Fiscal Year Final Research Report

• Project/Area Number: 21K16432
• 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: Kanamaru Rihito 自治医科大学, 医学部, 助教 (10625544)
• Project Period (FY): 2021-04-01 – 2023-03-31
• Keywords: 好中球細胞外トラップ / 免疫療法 / ケモタキシス / 細胞障害性T細胞 / CXCL-11 / 細胞運動 / 免疫チェックポイント阻害

Outline of Final Research Achievements

In vitro experiments showed that NETs produced by LPS-stimulated neutrophils efficiently cleaved CXCL11 via serine proteases and inhibited the infiltration of T lymphocytes activated with ant-CD3 and rIL-2. NETs were identified as CD66b(+)Cit-H3(+) cells by multicolor immunostaining of 138 resected specimens of high-grade serous ovarian cancer. The density of NETs was higher in advanced stage (p<0.05) and inversely correlated with the densities of CD4(+) or CD8(+) T cells (r=-0.5182, p<0.01; r=-0.5684, p<0.001, respectively). Postoperative progression-free survival (PFS) was significantly worse in the high NETs group (p<0.05), and the high NETs group was an independent predictor for worse PFS in multivariate analysis.It was suggested that NETs in solid tumors may efficiently degrade chemokines, suppress T lymphocyte infiltration, and promote cancer progression. Degradation of NETs may be used as a treatment method for solid cancer.

Free Research Field

消化器外科学・腫瘍免疫学

Academic Significance and Societal Importance of the Research Achievements

好中球が固形癌の進行に対して促進的な役割を果たすことは古くから指摘されているが、その機序は十分に解明されていない。本研究で、活性化好中球由来のNETsがケモカインを分解し、活性化Tリンパ球の浸潤を抑制することが判明し、NETsがその一因であることが新たに証明された。また、ヒト卵巣癌切除標本の免疫染色にて、NETsの量が、CD4(+)、CD8(+) T細胞の浸潤度、患者予後と逆相関することから、このメカニズムが実際にヒト癌でも存在する可能性があると考えられた。NETsの阻害が新たながん治療に繋がる可能性が得られたことから、その社会的意義は大きいと考えられる。