Immune cells constantly survey the host for pathogens or tumors and secrete cytokines to alert surrounding cells of these threats. In vivo, activated immune cells secrete cytokines for several hours, yet an acute immune reaction occurs over days. Given these divergent timescales, we addressed how cytokine-responsive cells translate brief cytokine exposure into phenotypic changes that persist over long timescales. We studied melanoma cell responses to transient exposure to the cytokine interferon gamma (IFNgamma) by combining a systems-scale analysis of gene expression dynamics with computational modeling and experiments. We discovered that IFNgamma is captured by phosphatidylserine (PS) on the surface of viable cells both in vitro and in vivo then slowly released to drive long-term transcription of cytokine-response genes. This mechanism introduces an additional function for PS in dynamically regulating inflammation across diverse cancer and primary cell types and has potential to usher in new immunotherapies targeting PS and inflammatory pathways.
Author Info: (1) ImmunoDynamics Group, Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA; Program in Immunology and Microbial
Author Info: (1) ImmunoDynamics Group, Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA; Program in Immunology and Microbial Pathogenesis, Weill Cornell Graduate School of Medical Sciences, New York, NY 10065, USA; Program in Computational Biology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (2) ImmunoDynamics Group, Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA; Physics Department, Ben Gurion University of the Negev, Beer-Sheva 84105, Israel. (3) Program in Physiology, Biophysics, and Systems Biology, Weill Cornell Graduate School of Medical Sciences, New York, NY 10065, USA. (4) ImmunoDynamics Group, Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA. (5) Laboratory of Host-Pathogen Dynamics, National Heart, Lung, and Blood Institute, Bethesda, MD 20892, USA. (6) Laboratory of Molecular Biology, Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA. (7) Physics Department, Ben Gurion University of the Negev, Beer-Sheva 84105, Israel; Ilse Kats Center for Nanoscience, Ben Gurion University of the Negev, Beer-Sheva 84105, Israel. (8) Laboratory of Host-Pathogen Dynamics, National Heart, Lung, and Blood Institute, Bethesda, MD 20892, USA. (9) ImmunoDynamics Group, Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA; Program in Immunology and Microbial Pathogenesis, Weill Cornell Graduate School of Medical Sciences, New York, NY 10065, USA; Program in Computational Biology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Program in Physiology, Biophysics, and Systems Biology, Weill Cornell Graduate School of Medical Sciences, New York, NY 10065, USA. Electronic address: gregoire.altan-bonnet@nih.gov.
