Authors: Megan M. Kaneda, Karen S. Messer, Natacha Ralainirina, Hongying Li, Chris Leem, Sara Gorjestani, Gyunghwi Woo, Abraham V. Nguyen, Camila C. Figueiredo, Philippe Foubert, Michael C. Schmid, Melissa Pink, David G. Winkler, Matthew Rausch, Vito J. Palombella, Jeffery Kutok, Karen McGovern, Kelly A. Frazer, Xuefeng Wu, Michael Karin, Roman Sasik, Ezra E. W. Cohen, Judith A. Varner
Summary:
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, while highly abundant 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 signaling through Akt and mTor inhibits NFκB activation while stimulating C/EBPβ activation, thereby inducing a transcriptional program that promotes immune suppression during inflammation and tumor growth. In 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 and synergizes with checkpoint inhibitor therapy to promote tumor regression and extend survival in mouse models of cancer. As PI3Kγ-directed, anti-inflammatory gene expression predicted survival probability in cancer patients, our findings demonstrate that therapeutic targeting of intracellular signaling pathways that regulate the switch between macrophage polarization states can control immune suppression in cancer and other disorders.
Source:
Nature; 2016