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

STING Pathway Activation Stimulates Potent Immunity against Acute Myeloid Leukemia.

Author information

1
Department of Medicine, University of Chicago, Chicago, IL 60637, USA.
2
Department of Pathology, University of Chicago, Chicago, IL 60637, USA.
3
Department of Medicine, University of Chicago, Chicago, IL 60637, USA; Committee on Immunology, University of Chicago, Chicago, IL 60637, USA.
4
Aduro Biotech, Inc., Berkeley, CA 94710, USA.
5
Department of Immuno-Oncology, Beckman Research Institute at City of Hope, Duarte, CA 91010, USA.
6
Department of Medicine, University of Chicago, Chicago, IL 60637, USA; Committee on Immunology, University of Chicago, Chicago, IL 60637, USA. Electronic address: jkline@medicine.bsd.uchicago.edu.

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.

PMID:
27264175
PMCID:
PMC5116809
DOI:
10.1016/j.celrep.2016.05.023
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

of Conflicts of Interest T.W.D is a paid employee of Aduro Biotech, holds stock in the company, and may be an inventor on patent applications that apply to the CDN molecules described in the manuscript.

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