title: PI3Kγ is a molecular switch that controls immune suppression.
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.
authors.affiliation: Moores Cancer Center, University of California, San Diego, La Jolla, California 92093, USA.
authors.forename: Megan M
authors.initials: MM
authors.lastname: Kaneda
authors.affiliation: Moores Cancer Center, University of California, San Diego, La Jolla, California 92093, USA.|Division of Biostatistics and Bioinformatics; Department of Family Medicine and Public Health University of California, San Diego, La Jolla, California 92093, USA.
authors.forename: Karen S
authors.initials: KS
authors.lastname: Messer
authors.affiliation: Moores Cancer Center, University of California, San Diego, La Jolla, California 92093, USA.
authors.forename: Natacha
authors.initials: N
authors.lastname: Ralainirina
authors.affiliation: Moores Cancer Center, University of California, San Diego, La Jolla, California 92093, USA.|Division of Biostatistics and Bioinformatics; Department of Family Medicine and Public Health University of California, San Diego, La Jolla, California 92093, USA.
authors.forename: Hongying
authors.initials: H
authors.lastname: Li
authors.affiliation: Moores Cancer Center, University of California, San Diego, La Jolla, California 92093, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Leem
authors.affiliation: Moores Cancer Center, University of California, San Diego, La Jolla, California 92093, USA.
authors.forename: Sara
authors.initials: S
authors.lastname: Gorjestani
authors.affiliation: Moores Cancer Center, University of California, San Diego, La Jolla, California 92093, USA.
authors.forename: Gyunghwi
authors.initials: G
authors.lastname: Woo
authors.affiliation: Moores Cancer Center, University of California, San Diego, La Jolla, California 92093, USA.
authors.forename: Abraham V
authors.initials: AV
authors.lastname: Nguyen
authors.affiliation: Moores Cancer Center, University of California, San Diego, La Jolla, California 92093, USA.|Dep. Biologia Celular, UERJ, Rio de Janeiro, 20550-013, Brazil.
authors.forename: Camila C
authors.initials: CC
authors.lastname: Figueiredo
authors.affiliation: Moores Cancer Center, University of California, San Diego, La Jolla, California 92093, USA.
authors.forename: Philippe
authors.initials: P
authors.lastname: Foubert
authors.affiliation: Moores Cancer Center, University of California, San Diego, La Jolla, California 92093, USA.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Schmid
authors.affiliation: Infinity Pharmaceuticals, Cambridge, Massachusetts 02139, USA.
authors.forename: Melissa
authors.initials: M
authors.lastname: Pink
authors.affiliation: Infinity Pharmaceuticals, Cambridge, Massachusetts 02139, USA.
authors.forename: David G
authors.initials: DG
authors.lastname: Winkler
authors.affiliation: Infinity Pharmaceuticals, Cambridge, Massachusetts 02139, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Rausch
authors.affiliation: Infinity Pharmaceuticals, Cambridge, Massachusetts 02139, USA.
authors.forename: Vito J
authors.initials: VJ
authors.lastname: Palombella
authors.affiliation: Infinity Pharmaceuticals, Cambridge, Massachusetts 02139, USA.
authors.forename: Jeffery
authors.initials: J
authors.lastname: Kutok
authors.affiliation: Infinity Pharmaceuticals, Cambridge, Massachusetts 02139, USA.
authors.forename: Karen
authors.initials: K
authors.lastname: McGovern
authors.affiliation: Department of Pediatrics, University of California, San Diego, La Jolla, California 92093, USA.|Institute for Genomic Medicine, University of California, San Diego, La Jolla, California 92093, USA.
authors.forename: Kelly A
authors.initials: KA
authors.lastname: Frazer
authors.affiliation: Department of Pharmacology, University of California, San Diego, La Jolla, California 92093, USA.
authors.forename: Xuefeng
authors.initials: X
authors.lastname: Wu
authors.affiliation: Department of Pharmacology, University of California, San Diego, La Jolla, California 92093, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Karin
authors.affiliation: Center for Computational Biology and Bioinformatics, Institute for Genomic Medicine, University of California, San Diego, La Jolla, California 92093, USA.
authors.forename: Roman
authors.initials: R
authors.lastname: Sasik
authors.affiliation: Moores Cancer Center, University of California, San Diego, La Jolla, California 92093, USA.|Department of Medicine, University of California, San Diego, La Jolla, California 92093, USA.
authors.forename: Ezra E W
authors.initials: EE
authors.lastname: Cohen
authors.affiliation: Moores Cancer Center, University of California, San Diego, La Jolla, California 92093, USA.|Department of Medicine, University of California, San Diego, La Jolla, California 92093, USA.|Department of Pathology, University of California, San Diego, La Jolla, California 92093, USA.
authors.forename: Judith A
authors.initials: JA
authors.lastname: Varner
mesh_terms: D000818:Animals; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000378:metabolism; D002478:Cells, Cultured; D058544:Class Ib Phosphatidylinositol 3-Kinase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology*; D007249:Inflammation / Q000276:immunology; D008213:Lymphocyte Activation; D008264:Macrophages / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D009369:Neoplasms / Q000276:immunology / Q000473:pathology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D019139:Tumor Escape / Q000276:immunology
chemical_list: D022782:CCAAT-Enhancer-Binding Protein-beta; D016328:NF-kappa B; C491383:Pdcd1 protein, mouse; D000081082:Phosphoinositide-3 Kinase Inhibitors; D061026:Programmed Cell Death 1 Receptor; C546843:mTOR protein, mouse; D058544:Class Ib Phosphatidylinositol 3-Kinase; C546764:Pik3cg protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases