Extrinsic Phagocyte-Dependent STING Signaling Dictates the Immunogenicity of Dying Cells

Cancer Cell. 2018 May 14;33(5):862-873.e5. doi: 10.1016/j.ccell.2018.03.027. Epub 2018 Apr 26.

Abstract

The ability of dying cells to activate antigen-presenting cells (APCs) is carefully controlled to avoid unwarranted inflammatory responses. Here, we show that engulfed cells containing cytosolic double-stranded DNA species (viral or synthetic) or cyclic di-nucleotides (CDNs) are able to stimulate APCs via extrinsic STING (stimulator of interferon genes) signaling, to promote antigen cross-presentation. In the absence of STING agonists, dying cells were ineffectual in the stimulation of APCs in trans. Cytosolic STING activators, including CDNs, constitute cellular danger-associated molecular patterns (DAMPs) only generated by viral infection or following DNA damage events that rendered tumor cells highly immunogenic. Our data shed insight into the molecular mechanisms that drive appropriate anti-tumor adaptive immune responses, while averting harmful autoinflammatory disease, and provide a therapeutic strategy for cancer treatment.

Keywords: STING; STING-dependent adjuvants (STAVs); anti-tumor T cells; antigen-presenting cells (APCs); cyclic di-nucleotides (CDNs); innate immunity; interferon.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antigen Presentation
  • Antigen-Presenting Cells / metabolism*
  • Cell Line, Tumor
  • DNA / genetics
  • HEK293 Cells
  • Humans
  • Melanoma, Experimental / genetics
  • Melanoma, Experimental / immunology*
  • Membrane Proteins / genetics*
  • Membrane Proteins / metabolism
  • Mice
  • Nucleotides, Cyclic / genetics*
  • Phagocytes / immunology*
  • Signal Transduction
  • Transfection

Substances

  • Membrane Proteins
  • Nucleotides, Cyclic
  • Sting1 protein, mouse
  • DNA