期刊
JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE
卷 106, 期 8, 页码 -出版社
OXFORD UNIV PRESS INC
DOI: 10.1093/jnci/dju162
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资金
- Anthony Bullock III Foundation
- Cynthia and George Mitchell Foundation
- Dr. Marnie Rose Foundation
- Vaughn Foundation
- National Institutes of Health [CA120813-01, P50 CA127001]
- National Institutes of Health (MDACC Brain SPORE Career Developmental Grant) [K08 NS070928]
Background The immune therapeutic potential of microRNAs (miRNAs) in the context of tumor-mediated immune suppression has not been previously described for monocyte-derived glioma-associated macrophages, which are the largest infiltrating immune cell population in glioblastomas and facilitate gliomagenesis. Methods An miRNA microarray was used to compare expression profiles between human glioblastoma-infiltrating macrophages and matched peripheral monocytes. The effects of miR-142-3p on phenotype and function of proinflammatory M1 and immunosuppressive M2 macrophages were determined. The therapeutic effect of miR-142-3p was ascertained in immune-competent C57BL/6J mice harboring intracerebral GL261 gliomas and in genetically engineered Ntv-a mice bearing high-grade gliomas. Student t test was used to evaluate the differences between ex vivo datasets. Survival was analyzed with the log-rank test and tumor sizes with linear mixed models and F test. All statistical tests were two-sided. Results miR-142-3p was the most downregulated miRNA (approximately 4.95-fold) in glioblastoma-infiltrating macrophages. M2 macrophages had lower miR-142-3p expression relative to M1 macrophages (P =.03). Overexpression of miR-142-3p in M2 macrophages induced selective modulation of transforming growth factor beta receptor 1, which led to subsequent preferential apoptosis in the M2 subset (P = .01). In vivo miR-142-3p administration resulted in glioma growth inhibition (P = .03, n = 5) and extended median survival (miR-142-3p-treated C57BL/6J mice vs scramble control: 31 days vs 23.5 days, P =.03, n = 10; miR-142-3p treated Ntv-a mice vs scramble control: 32 days vs 24 days, P =.03, n = 9), with an associated decrease in infiltrating macrophages (R-2 =.303). Conclusions These data indicate a unique role of miR-142-3p in glioma immunity by modulating M2 macrophages through the transforming growth factor beta signaling pathway.
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