STING-dependent Cytosolic DNA Sensing Mediates Innate Immune Recognition of Immunogenic Tumors

Immunity. 2014 Nov 20;41(5):830-42. doi: 10.1016/j.immuni.2014.10.017. Epub 2014 Nov 5.

Abstract

Spontaneous T cell responses against tumors occur frequently and have prognostic value in patients. The mechanism of innate immune sensing of immunogenic tumors leading to adaptive T cell responses remains undefined, although type I interferons (IFNs) are implicated in this process. We found that spontaneous CD8(+) T cell priming against tumors was defective in mice lacking stimulator of interferon genes complex (STING), but not other innate signaling pathways, suggesting involvement of a cytosolic DNA sensing pathway. In vitro, IFN-? production and dendritic cell activation were triggered by tumor-cell-derived DNA, via cyclic-GMP-AMP synthase (cGAS), STING, and interferon regulatory factor 3 (IRF3). In the tumor microenvironment in vivo, tumor cell DNA was detected within host antigen-presenting cells, which correlated with STING pathway activation and IFN-? production. Our results demonstrate that a major mechanism for innate immune sensing of cancer occurs via the host STING pathway, with major implications for cancer immunotherapy.

Publication types

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

MeSH terms

  • Adaptive Immunity
  • Adaptor Proteins, Signal Transducing / genetics
  • Adoptive Transfer
  • Animals
  • Antigen-Presenting Cells / cytology
  • Antigen-Presenting Cells / immunology
  • CD8-Positive T-Lymphocytes / immunology*
  • Cell Line, Tumor
  • Cell Proliferation
  • DNA / immunology*
  • Dendritic Cells / immunology
  • Immunity, Innate
  • Interferon Regulatory Factor-3 / genetics
  • Interferon-beta / biosynthesis
  • Lymphocyte Activation / immunology*
  • Melanoma, Experimental / immunology*
  • Membrane Proteins / genetics
  • Membrane Proteins / immunology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Myeloid Differentiation Factor 88 / genetics
  • Nucleotidyltransferases
  • Receptors, Antigen, T-Cell / immunology
  • Receptors, Purinergic P2X7 / genetics
  • Toll-Like Receptor 4 / genetics
  • Toll-Like Receptor 9 / genetics
  • Tumor Microenvironment / immunology

Substances

  • Adaptor Proteins, Signal Transducing
  • IPS-1 protein, mouse
  • Interferon Regulatory Factor-3
  • Irf3 protein, mouse
  • MPYS protein, mouse
  • Membrane Proteins
  • Myd88 protein, mouse
  • Myeloid Differentiation Factor 88
  • Receptors, Antigen, T-Cell
  • Receptors, Purinergic P2X7
  • Tlr4 protein, mouse
  • Tlr9 protein, mouse
  • Toll-Like Receptor 4
  • Toll-Like Receptor 9
  • Interferon-beta
  • DNA
  • Nucleotidyltransferases
  • cGAS protein, mouse

Associated data

  • GEO/GSE61835