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.
Seng-Ryong Woo  1 ,  Mercedes B Fuertes  1 ,  Leticia Corrales  1 ,  Stefani Spranger  1 ,  Michael J Furdyna  1 ,  Michael Y K Leung  1 ,  Ryan Duggan  2 ,  Ying Wang  3 ,  Glen N Barber  4 ,  Katherine A Fitzgerald  5 ,  Maria-Luisa Alegre  3 ,  Thomas F Gajewski  6
Affiliations
  • 1. Department of Pathology, The University of Chicago, 929 E57th Street GCIS W423H, Chicago, IL 60637, USA.
  • 2. Flow Cytometry Core Facility, The University of Chicago, 924 E57th Street r022, Chicago, IL 60637, USA.
  • 3. Department of Medicine, The University of Chicago, 5841 South Maryland Avenue, MC6092, Chicago, IL 60637, USA.
  • 4. Department of Cell Biology, University of Miami, Rosenstiel Medical Science Building, 4th Floor 1600 N.W. 10th Avenue, Miami, FL 33136, USA.
  • 5. Department of Infectious Diseases and Immunology, University of Massachusetts, 364 Plantation Street, LRB, Worcester, MA 01605, USA.
  • 6. Department of Pathology, The University of Chicago, 929 E57th Street GCIS W423H, Chicago, IL 60637, USA; Department of Medicine, The University of Chicago, 5841 South Maryland Avenue, MC6092, Chicago, IL 60637, USA. Electronic address: [email protected].
PMID: 25517615 DOI: 10.1016/j.immuni.2014.10.017
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.