PI3Kγ is a molecular switch that controls immune suppression

Modulation of PI3Kγ activity regulates macrophage polarization during inflammation and cancer, whilst combining PI3Kγ inhibition with immune checkpoint inhibitors leads to synergistic tumour-inhibitory effects. Macrophages are specialized immune cells that can either stimulate or inhibit inflammation. Here Judith Varner and colleagues provide evidence that the activation state of a single macrophage kinase, the PI 3-kinase γ (PI3Kγ) isoform, can control the switch between immune suppression and immune stimulation in cancer and inflammatory disease. PI3Kγ inhibition abates the immunosuppressive functions of tumour-associated macrophages to promote T-cell cytotoxicity. Combining PI3Kγ inhibition with immune checkpoint blockade leads to additive or synergistic tumour-inhibitory effects. This work suggests that that inhibitory targeting of macrophage signalling pathways may provide a novel approach to improving long-term survival of cancer patients. 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.