PI3Kγ is a molecular switch that controls immune suppression

Autor: Karen McGovern, Xuefeng Wu, Roman Sasik, Ezra E.W. Cohen, Matthew Rausch, Christopher J. Leem, Megan M. Kaneda, Kelly A. Frazer, Jeffery L. Kutok, David G. Winkler, Natacha Ralainirina, Michael C. Schmid, Melissa Pink, Gyunghwi Woo, Philippe Foubert, Judith A. Varner, Camila C. Figueiredo, Vito J. Palombella, Karen Messer, Abraham V. Nguyen, Hongying Li, Sara Gorjestani, Michael Karin
Rok vydání: 2016
Předmět:
0301 basic medicine
Male
T-Lymphocytes
Programmed Cell Death 1 Receptor
Inbred C57BL
Lymphocyte Activation
Mice
0302 clinical medicine
Neoplasms
Macrophage
Cytotoxic T cell
Class Ib Phosphatidylinositol 3-Kinase
Cells
Cultured
Cancer
Phosphoinositide-3 Kinase Inhibitors
Cultured
Multidisciplinary
TOR Serine-Threonine Kinases
NF-kappa B
Cell biology
medicine.anatomical_structure
030220 oncology & carcinogenesis
Female
Immunotherapy
medicine.symptom
Signal Transduction
General Science & Technology
Cells
T cell
Macrophage polarization
Inflammation
Biology
Article
03 medical and health sciences
Immune system
medicine
Immune Tolerance
Animals
Humans
PI3K/AKT/mTOR pathway
Immunosuppression Therapy
Innate immune system
CCAAT-Enhancer-Binding Protein-beta
Macrophages
Mice
Inbred C57BL
030104 developmental biology
Tumor Escape
Proto-Oncogene Proteins c-akt
Zdroj: Nature, vol 539, iss 7629
Nature
ISSN: 1476-4687
Popis: 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.
Databáze: OpenAIRE
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