Catch and Release of Cytokines Mediated by Tumor Phosphatidylserine Converts Transient Exposure into Long-Lived Inflammation

• Published in: Molecular cell 2017-06, Vol.66 (5), p.635-647.e7
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Animals; Cell Communication; Cell Line, Tumor; Coculture Techniques; Computational Biology; Computer Simulation; cytokine signaling; Databases, Genetic; Female; Gene Expression Profiling - methods; Gene Expression Regulation, Neoplastic; HEK293 Cells; Humans; IFNγ; Inflammation - genetics; Inflammation - immunology; Inflammation - metabolism; Inflammation - pathology; Inflammation Mediators - metabolism; Interferon gamma Receptor; Interferon-gamma - immunology; Interferon-gamma - metabolism; Interleukin-12 - immunology; Interleukin-12 - metabolism; Interleukin-23 - immunology; Interleukin-23 - metabolism; Janus Kinases - metabolism; Lymphocyte Activation; Lymphocytes, Tumor-Infiltrating - immunology; Lymphocytes, Tumor-Infiltrating - metabolism; Lymphocytes, Tumor-Infiltrating - pathology; Male; Melanoma, Experimental - genetics; Melanoma, Experimental - immunology; Melanoma, Experimental - metabolism; Melanoma, Experimental - pathology; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Models, Biological; phosphatidylserine; Phosphatidylserines - immunology; Phosphatidylserines - metabolism; Phosphorylation; PTEN Phosphohydrolase - genetics; PTEN Phosphohydrolase - metabolism; quantitative biology; RAW 264.7 Cells; Receptors, Interferon - genetics; Receptors, Interferon - metabolism; Signal Transduction; STAT1 Transcription Factor - metabolism; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; T-Lymphocytes - pathology; Thyroid Neoplasms - genetics; Thyroid Neoplasms - immunology; Thyroid Neoplasms - metabolism; Thyroid Neoplasms - pathology; Time Factors; Transcription, Genetic; transcriptional regulation; tumor inflammation; tumor microenvironment
• ISSN: 1097-2765; 1097-4164
• 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. [Display omitted] •Transient IFNγ exposure elicits long-lived inflammatory responses in cancer cells•Long-lived inflammatory responses are caused by persistent cytokine signaling•Long-lived IFNγ signaling is mediated by catch and release of cytokines•Cytokines are captured by cell-surface-exposed phosphatidylserine and then recycled Activated immune cells secrete cytokines for only a few hours, yet acute immune reactions unfold over a week or more. Oyler-Yaniv et al. resolve this timescale discrepancy by uncovering how cancer and immune cells rely on their surface phosphatidylserine to capture cytokines then slowly release them, eliciting long-term cell-to-cell communication.