PI3Kγ is a molecular switch that controls immune suppression


Kaneda, MM, Messer, KS, Ralainirina, N, Li, H, Leem, CJ, Gorjestani, S, Woo, G, Nguyen, AV, Figueiredo, CC, Foubert, P et al (show 13 more authors) (2016) PI3Kγ is a molecular switch that controls immune suppression. Nature, 539 (7629). pp. 437-442.

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Abstract

Macrophages play critical, but opposite, roles in acute and chronic inflammation and cancer1,2,3,4,5. 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 inhibitors1,2,3,4,5,6,7. 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.

Item Type: Article
Uncontrolled Keywords: immunosuppression, immunosurveillance, inflammation, innate immunity
Depositing User: Symplectic Admin
Date Deposited: 04 Nov 2016 11:41
Last Modified: 19 Jan 2023 07:26
DOI: 10.1038/nature19834
Related URLs:
URI: https://livrepository.liverpool.ac.uk/id/eprint/3004369
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