PI3K/AKT/mTOR通路
免疫系统
巨噬细胞极化
炎症
细胞毒性T细胞
生物
巨噬细胞
蛋白激酶B
CD8型
T细胞
免疫学
信号转导
细胞生物学
癌症研究
生物化学
体外
作者
Megan M. Kaneda,Karen Messer,Natacha Ralainirina,Hongying Li,Christopher J. Leem,Sara Gorjestani,Gyunghwi Woo,Abraham V. Nguyen,Camila C. Figueiredo,Philippe Foubert,Michael C. Schmid,Melissa Pink,David G. Winkler,Matthew Rausch,Vito J. Palombella,Jeffery L. Kutok,Karen McGovern,Kelly A. Frazer,Xuefeng Wu,Michael Karin,Roman Šášik,Ezra E.W. Cohen,Judith A. Varner
出处
期刊:Nature
[Springer Nature]
日期:2016-09-19
卷期号:539 (7629): 437-442
被引量:845
摘要
Macrophages play critical, but opposite, roles in acute and chronic inflammation and cancer. In response to pathogens or injury, inflammatory macrophages express cytokines that stimulate cytotoxic T cells, whereas macrophages in neoplastic and parasitic diseases express anti-inflammatory cytokines that induce immune suppression and may promote resistance to T cell checkpoint inhibitors. Here we show that macrophage PI 3-kinase γ controls a critical switch between immune stimulation and suppression during inflammation and cancer. PI3Kγ signalling through Akt and mTor inhibits NFκB activation while stimulating C/EBPβ activation, thereby inducing a transcriptional program that promotes immune suppression during inflammation and tumour growth. By contrast, selective inactivation of macrophage PI3Kγ stimulates and prolongs NFκB activation and inhibits C/EBPβ activation, thus promoting an immunostimulatory transcriptional program that restores CD8+ T cell activation and cytotoxicity. PI3Kγ synergizes with checkpoint inhibitor therapy to promote tumour regression and increased survival in mouse models of cancer. In addition, PI3Kγ-directed, anti-inflammatory gene expression can predict survival probability in cancer patients. Our work thus demonstrates that therapeutic targeting of intracellular signalling pathways that regulate the switch between macrophage polarization states can control immune suppression in cancer and other disorders.
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