医学
胶质瘤
癌症研究
M2巨噬细胞
巨噬细胞极化
体内
肿瘤微环境
流式细胞术
巨噬细胞
外周血单个核细胞
人口
细胞因子
体外
免疫学
生物
肿瘤细胞
生物化学
生物技术
环境卫生
作者
Michelot Michel,Liron L. Israel,Miguel Eduardo Tusa Lavieri,Hongqiang Wang,Ken Miyaguchi,Sarah Mohyeddinipour,Junji Watanabe,Keith L. Black,Ramachandran Murali,John S. Yu
出处
期刊:Neurosurgery
[Oxford University Press]
日期:2024-04-01
卷期号:70 (Supplement_1): 64-64
标识
DOI:10.1227/neu.0000000000002809_235
摘要
INTRODUCTION: Glioblastoma (GBM) is the most aggressive primary brain malignancy with a median survival of 14 months. Tumor-associated macrophages (TAMs) comprise up to 40% of the GBM tumor mass and are significant enablers of an immunosuppressive tumor microenvironment (TME), limiting immunotherapeutic efficacy. TAMs are generally classified as M2 macrophages that demonstrate a pro-tumor phenotype and increased CD206 surface marker expression. Reducing the M2 macrophage population in tumors has shown benefit in preclinical studies across various cancers. Interleukins (IL)-4 and -13 both play a role in polarizing macrophages to an M2 state. We developed a peptide inhibitor (KROS-401) that targets the shared IL-4Ra subunit of the IL-4 and -13 receptor complex to inhibit macrophage polarization to an M2 phenotype and reprogram the immunosuppressive TME. METHODS: Human peripheral blood mononuclear cell (PBMC)-derived macrophages were isolated and treated with KROS-401 in the presence of IL-4 and IL-13 cytokines. M2 (CD206) surface markers were assessed by flow cytometry. The efficacy of KROS-401 peptide was examined using an intracranially implanted syngeneic murine model with luciferase-expressing GL261, a glioma cell line. Mice were inspected daily for survival and tumor growth was tracked by non-invasive in vivo bioluminescent imaging (BLI). RESULTS: Human PBMC-derived macrophages treated with KROS-401 displayed a dose-dependent decrease in M2 (CD206) cell surface markers. KROS-401 peptide inhibitor demonstrated anti-tumor activity in GL261 glioma-bearing mice with a significantly increased probability of survival compared to control (p = 0.0046) with a median survival of >40 days versus 27 days, respectively. CONCLUSIONS: KROS-401 inhibits M2 polarization of human macrophages in vitro and tumor growth in vivo. These findings highlight this IL-4/IL-13 peptide inhibitor as a potential immunomodulator of the TME for the treatment of GBM.
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