STING Pathway Activation Stimulates Potent Immunity against Acute Myeloid Leukemia

Cell Rep. 2016 Jun 14;15(11):2357-66. doi: 10.1016/j.celrep.2016.05.023. Epub 2016 Jun 2.

Abstract

Type I interferon (IFN), essential for spontaneous T cell priming against solid tumors, is generated through recognition of tumor DNA by STING. Interestingly, we observe that type I IFN is not elicited in animals with disseminated acute myeloid leukemia (AML). Further, survival of leukemia-bearing animals is not diminished in the absence of type I IFN signaling, suggesting that STING may not be triggered by AML. However, the STING agonist, DMXAA, induces expression of IFN-β and other inflammatory cytokines, promotes dendritic cell (DC) maturation, and results in the striking expansion of leukemia-specific T cells. Systemic DMXAA administration significantly extends survival in two AML models. The therapeutic effect of DMXAA is only partially dependent on host type I IFN signaling, suggesting that other cytokines are important. A synthetic cyclic dinucleotide that also activates human STING provided a similar anti-leukemic effect. These data demonstrate that STING is a promising immunotherapeutic target in AML.

Publication types

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

MeSH terms

  • Adaptive Immunity / drug effects
  • Animals
  • Antigen-Presenting Cells / drug effects
  • Antigen-Presenting Cells / metabolism
  • Antigens, Neoplasm / immunology
  • CD8-Positive T-Lymphocytes / immunology
  • Cell Line, Tumor
  • Disease Models, Animal
  • Genetic Engineering
  • Humans
  • Immunity, Innate* / drug effects
  • Immunologic Memory / drug effects
  • Interferon Type I / metabolism
  • Leukemia, Myeloid, Acute / immunology*
  • Leukemia, Myeloid, Acute / pathology
  • Membrane Proteins / metabolism*
  • Mice, Inbred C57BL
  • Signal Transduction / drug effects*
  • Survival Analysis
  • Xanthones / pharmacology

Substances

  • Antigens, Neoplasm
  • Interferon Type I
  • MPYS protein, mouse
  • Membrane Proteins
  • Xanthones
  • vadimezan