Macrophage Role in Infection Determined by PI-3 Kinase-Gamma Signaling

Cancer researchers have identified a molecule responsible for the signal that converts macrophages from an inflammatory, immunostimulatory mode in acute infections to an anti-inflammatory, immunosuppressive mode that supports tumor development and growth.

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 cancer and parasitic diseases express anti-inflammatory cytokines that induce immune suppression and may promote tumor growth.

Investigators at the University of California, San Diego (USA) reported in the September 19, 2016, online issue of the journal Nature that results of experiments carried out with mouse models had allowed them to identify the macrophage enzyme PI-3 kinase-gamma (PI3K-gamma) as the controller of a critical switch between immune stimulation and suppression during inflammation and cancer.

PI3K-gamma signaling induced a transcriptional program that promoted immune suppression during inflammation and tumor growth. In contrast, selective inactivation of macrophage PI3K-gamma promoted an immunostimulatory transcriptional program that restored CD8+ T-cell activation and cytotoxicity and synergized with checkpoint inhibitor therapy to promote tumor regression and extend survival in mouse models of cancer.

“Immunotherapies, such as T-cell checkpoint inhibitors, are showing great promise in early treatments and trials, but they are not universally effective,” said senior author Dr. Judith A. Varner, professor of pathology and medicine at the University of California, San Diego. “We have identified a new method to boost the effectiveness of current immune therapy. Our findings also improve our understanding of key mechanisms that control cancer immune suppression and could lead to the development of more effective immunotherapies.”

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