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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.

Inhibitor of [kappa]B (I[kappa]B) kinase (IKK) phosphorylates I[kappa]B proteins, leading to their degradation and the liberation of nuclear factor [kappa]B for gene transcription. Here we report the crystal structure of IKK[beta] in complex with an inhibitor, at a resolution of 3.6 Å. The structure reveals a trimodular architecture comprising the kinase domain, a ubiquitin-like domain (ULD) and an elongated, [alpha]-helical scaffold/dimerization domain (SDD). Unexpectedly, the predicted leucine zipper and helix-loop-helix motifs do not form these structures but are part of the SDD. The ULD and SDD mediate a critical interaction with I[kappa]B[alpha] that restricts substrate specificity, and the ULD is also required for catalytic activity. The SDD mediates IKK[beta] dimerization, but dimerization per se is not important for maintaining IKK[beta] activity and instead is required for IKK[beta] activation. Other IKK family members, IKK[alpha], TBK1 and IKK-i, may have a similar trimodular architecture and function. Structure of inhibitor of [kappa]B kinase IKK (inhibitor of [kappa]B kinase) is an important element in the activation of nuclear factor [kappa]B (NF-[kappa]B) transcription factors -- master regulators of inflammatory, immune and apoptotic responses. Here Wu and colleagues describe the long awaited X-ray structure of a member of the IKK family in combination with an inhibitor. They show that IKK[beta] has a tri-molecular architecture that contains the kinase domain, a ubiquitin-like domain and an extended scaffolding and dimerization domain, and discuss the functional implications., Author(s): Guozhou Xu [sup.1] , Yu-Chih Lo [sup.1] , Qiubai Li [sup.1] , Gennaro Napolitano [sup.2] , Xuefeng Wu [sup.2] , Xuliang Jiang [sup.3] , Michel Dreano [sup.4] , Michael [...]