| First Author | Kaneda MM | Year | 2016 |
| Journal | Nature | Volume | 539 |
| Issue | 7629 | Pages | 437-442 |
| PubMed ID | 27642729 | Mgi Jnum | J:241320 |
| Mgi Id | MGI:5901797 | Doi | 10.1038/nature19834 |
| Citation | Kaneda MM, et al. (2016) PI3Kgamma is a molecular switch that controls immune suppression. Nature 539(7629):437-442 |
| abstractText | 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 gamma controls a critical switch between immune stimulation and suppression during inflammation and cancer. PI3Kgamma signalling through Akt and mTor inhibits NFkappaB activation while stimulating C/EBPbeta activation, thereby inducing a transcriptional program that promotes immune suppression during inflammation and tumour growth. By contrast, selective inactivation of macrophage PI3Kgamma stimulates and prolongs NFkappaB activation and inhibits C/EBPbeta activation, thus promoting an immunostimulatory transcriptional program that restores CD8+ T cell activation and cytotoxicity. PI3Kgamma synergizes with checkpoint inhibitor therapy to promote tumour regression and increased survival in mouse models of cancer. In addition, PI3Kgamma-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. |
