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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / pharmacology*
  • Blotting, Western
  • Cell Line, Tumor
  • Enzyme-Linked Immunosorbent Assay
  • Gene Knockout Techniques
  • Humans
  • Macrophages
  • Membrane Proteins / antagonists & inhibitors*
  • Membrane Proteins / immunology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Neoplasms, Experimental / drug therapy
  • Neoplasms, Experimental / immunology*
  • Nucleotides, Cyclic / chemical synthesis
  • Nucleotides, Cyclic / pharmacology*
  • Polymerase Chain Reaction
  • Transfection
  • Tumor Microenvironment / immunology*
  • Xanthones / pharmacology

Substances

  • Antineoplastic Agents
  • MPYS protein, mouse
  • Membrane Proteins
  • Nucleotides, Cyclic
  • Xanthones
  • vadimezan