Oyler-Yaniv Jennifer, Oyler-Yaniv Alon, Shakiba Mojdeh, Min Nina K, Chen Ying-Han, Cheng Sheue-Yann, Krichevsky Oleg, Altan-Bonnet Nihal, Altan-Bonnet Grégoire
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.
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.
Mol Cell. 2017 Jun 1;66(5):635-647.e7. doi: 10.1016/j.molcel.2017.05.011.
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 γ (IFNγ) by combining a systems-scale analysis of gene expression dynamics with computational modeling and experiments. We discovered that IFNγ 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.
免疫细胞不断监测宿主体内的病原体或肿瘤，并分泌细胞因子以提醒周围细胞注意这些威胁。在体内，活化的免疫细胞会分泌数小时的细胞因子，但急性免疫反应会持续数天。考虑到这些不同的时间尺度，我们研究了细胞因子反应性细胞如何将短暂的细胞因子暴露转化为长期持续的表型变化。我们通过结合基因表达动力学的系统规模分析、计算建模和实验，研究了黑色素瘤细胞对细胞因子干扰素γ（IFNγ）短暂暴露的反应。我们发现，在体外和体内，IFNγ都被活细胞表面的磷脂酰丝氨酸（PS）捕获，然后缓慢释放，以驱动细胞因子反应基因的长期转录。这种机制为PS在动态调节多种癌症和原代细胞类型的炎症方面引入了额外功能，并且有可能带来针对PS和炎症途径的新免疫疗法。
