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

Jennifer Oyler-Yaniv, Alon Oyler-Yaniv, Mojdeh Shakiba, Nina K. Min, Ying Han Chen, Sheue yann Cheng, Oleg Krichevsky, Nihal Altan-Bonnet, Grégoire Altan-Bonnet

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)635-647.e7
JournalMolecular Cell
Volume66
Issue number5
DOIs
StatePublished - 1 Jun 2017

Keywords

  • IFNγ
  • cytokine signaling
  • phosphatidylserine
  • quantitative biology
  • transcriptional regulation
  • tumor inflammation
  • tumor microenvironment

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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