PI3K is a molecular switch that controls immune suppression

Macrophages play critical, but opposite, roles in acute and chronic inflammation and cancer1-5. 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 cytokine...

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Bibliographic Details
Published in:Nature (London) 2016-11, Vol.539 (7629), p.437
Main Authors: Kaneda, Megan M, Messer, Karen S, Ralainirina, Natacha, Li, Hongying, Leem, Christopher J, Gorjestani, Sara, Woo, Gyunghwi, Nguyen, Abraham V, Figueiredo, Camila C, Foubert, Philippe, Schmid, Michael C, Pink, Melissa, Winkler, David G, Rausch, Matthew, Palombella, Vito J, Kutok, Jeffery, McGovern, Karen, Frazer, Kelly A, Wu, Xuefeng, Karin, Michael, Sasik, Roman, Cohen, Ezra E. W, Varner, Judith A
Format: Article
Language:English
Subjects:
Cancer
Cytokines
Cytotoxicity
Deoxyribonucleic acid
DNA
Gene expression
Genomes
Health aspects
Human papillomavirus
Immune response
Inactivation
Inflammation
Kinases
Leukocytes
Macrophages
Molecular motors (Biochemistry)
Observations
Phosphorylation
Proteins
Studies
Tumors
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Summary:Macrophages play critical, but opposite, roles in acute and chronic inflammation and cancer1-5. 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 inhibitors1-7. Here we show that macrophage PI 3-kinase [gamma] controls a critical switch between immune stimulation and suppression during inflammation and cancer. PI3K[gamma] signalling through Akt and mTOR inhibits NF[kappa]B activation while stimulating C/EBP[beta] activation, thereby inducing a transcriptional program that promotes immune suppression during inflammation and tumour growth. By contrast, selective inactivation of macrophage PI3K[gamma] stimulates and prolongs NF[kappa]B activation and inhibits C/EBP[beta] activation, thus promoting an immunostimulatory transcriptional program that restores CD8^sup +^ T cell activation and cytotoxicity. PI3K[gamma] synergizes with checkpoint inhibitor therapy to promote tumour regression and increased survival in mouse models of cancer. In addition, PI3K[gamma]-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.
ISSN:0028-0836
1476-4687
DOI:10.1038/nature19834