Macrophages play critical role in acute and chronic inflammation and cancer. In response to pathogens or injury, inflammatory macrophages express cytokines that stimulate cytotoxic T cells. Macrophage PI(3)Kinase γ controls a critical switch between immune stimulation and suppression during inflammation and cancer. PI3KC signaling through Akt and mTor inhibits NFκB activation while stimulating C/EBPβ activation. This induces a transcriptional program that promotes immune suppression during inflammation and tumor growth. However, 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 and synergizes with checkpoint inhibitor therapy to promote tumor regression and extend survival. The therapeutic targeting of intracellular signaling pathways that regulate the switch between macrophage polarization states can control immune suppression in cancer and other disorders.
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