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Nature. 2016 Nov 17;539(7629):437-442. doi: 10.1038/nature19834. Epub 2016 Sep 19.

PI3Kγ is a molecular switch that controls immune suppression.

Author information

1
Moores Cancer Center, University of California, San Diego, La Jolla, California 92093, USA.
2
Division of Biostatistics and Bioinformatics; Department of Family Medicine and Public Health University of California, San Diego, La Jolla, California 92093, USA.
3
Dep. Biologia Celular, UERJ, Rio de Janeiro, 20550-013, Brazil.
4
Infinity Pharmaceuticals, Cambridge, Massachusetts 02139, USA.
5
Department of Pediatrics, University of California, San Diego, La Jolla, California 92093, USA.
6
Institute for Genomic Medicine, University of California, San Diego, La Jolla, California 92093, USA.
7
Department of Pharmacology, University of California, San Diego, La Jolla, California 92093, USA.
8
Center for Computational Biology and Bioinformatics, Institute for Genomic Medicine, University of California, San Diego, La Jolla, California 92093, USA.
9
Department of Medicine, University of California, San Diego, La Jolla, California 92093, USA.
10
Department of Pathology, University of California, San Diego, La Jolla, California 92093, USA.

Abstract

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.

PMID:
27642729
PMCID:
PMC5479689
DOI:
10.1038/nature19834
[Indexed for MEDLINE]
Free PMC Article

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