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Cell Rep. 2015 May 19;11(7):1018-30. doi: 10.1016/j.celrep.2015.04.031. Epub 2015 May 7.

Direct Activation of STING in the Tumor Microenvironment Leads to Potent and Systemic Tumor Regression and Immunity.

Author information

  • 1Department of Pathology, The University of Chicago, 929 E57th Street GCIS 3H, Chicago, IL 60637, USA.
  • 2Aduro BioTech, Inc., 626 Bancroft Way, 3C, Berkeley, CA 94710, USA.
  • 3Aduro BioTech, Inc., 626 Bancroft Way, 3C, Berkeley, CA 94710, USA. Electronic address: tdubensky@aduro.com.
  • 4Department of Pathology, The University of Chicago, 929 E57th Street GCIS 3H, Chicago, IL 60637, USA. Electronic address: tgajewsk@medicine.bsd.uchicago.edu.

Abstract

Spontaneous tumor-initiated T cell priming is dependent on IFN-β production by tumor-resident dendritic cells. On the basis of recent observations indicating that IFN-β expression was dependent upon activation of the host STING pathway, we hypothesized that direct engagement of STING through intratumoral (IT) administration of specific agonists would result in effective anti-tumor therapy. After proof-of-principle studies using the mouse STING agonist DMXAA showed a potent therapeutic effect, we generated synthetic cyclic dinucleotide (CDN) derivatives that activated all human STING alleles as well as murine STING. IT injection of STING agonists induced profound regression of established tumors in mice and generated substantial systemic immune responses capable of rejecting distant metastases and providing long-lived immunologic memory. Synthetic CDNs have high translational potential as a cancer therapeutic.

PMID:
25959818
PMCID:
PMC4440852
DOI:
10.1016/j.celrep.2015.04.031
[PubMed - indexed for MEDLINE]
Free PMC Article
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