PI3Kγ is a molecular switch that controls immune suppression
By Megan M. Kaneda, K. Messer, N. Ralainirina, Hongying Li, Christopher J. Leem, Sara Gorjestani, Gyunghwi Woo, A. V. Nguyen, C. C. Figueiredo, P. Foubert and 13 more. Nature, 2016
1,084 citations recorded by the source corpus.
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.
Subfields: Immunology
View Paper: https://www.semanticscholar.org/paper/f14cb37c2fcbb1e429885946ff3883b48653a968
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In Immunology
Citations in the corpus
- Macrophage Polarization: Different Gene Signatures in M1(LPS+) vs. Classically and M2(LPS–) vs. Alternatively Activated Macrophages (2019, background): “M1 polarizers show preclinical evidence of improving cancer outcomes (99, 100).”
- Tumor and Microenvironment Evolution during Immunotherapy with Nivolumab (2017, result): “Notably, this analysis identified numerous HLA class II genes, along with other genes, as differentially expressed and this is similar to a recently reported signature indicating differences in regulation of macrophages (Kaneda et al., 2016).”
- Immunosuppression mediated by myeloid-derived suppressor cells (MDSCs) during tumour progression (2018, positive): “PI3K activation leads to the inhibition of NF-κB and activation of C/EBPβ, thereby initiating an immunosuppressive transcriptional program.(110) Knockout of PI3K was found to reduce the accumulation of PMN-MDSC in tumour-bearing mice, breaking immune tolerance to cancer.”
- Hypoxic Tumor-Derived Exosomal miR-301a Mediates M2 Macrophage Polarization via PTEN/PI3Kγ to Promote Pancreatic Cancer Metastasis. (2018, background): “PI3K/AKT/mTOR signaling pathway was closely related to macrophage activation and polarization (27, 45).”
- Targeting PI3K in cancer: mechanisms and advances in clinical trials (2019, background): “PI3Kγ is abundantly expressed in immune cells of myeloid origin but not cancer cells, which regulates innate immunity in both inflammation and cancer [55].”
- Progress in tumor-associated macrophage (TAM)-targeted therapeutics (2017, positive): “recently showed that PI3kγ inhibitor (IPI-549) retarded tumor growth in implanted human papilloma virus positive head and neck squamous cell carcinoma (HPV+HNSCC), lung carcinoma, and breast carcinoma models in a TAMdependent manner by promoting TAM-immunostimulatory responses [130].”