STING Pathway Activation Stimulates Potent Immunity against Acute Myeloid Leukemia.
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.
Department of Medicine, University of Chicago, Chicago, IL 60637, USA.
Emily
E
Curran
Department of Medicine, University of Chicago, Chicago, IL 60637, USA.
Xiufen
X
Chen
Department of Pathology, University of Chicago, Chicago, IL 60637, USA.
Leticia
L
Corrales
Department of Medicine, University of Chicago, Chicago, IL 60637, USA; Committee on Immunology, University of Chicago, Chicago, IL 60637, USA.
Douglas E
DE
Kline
Aduro Biotech, Inc., Berkeley, CA 94710, USA.
Thomas W
TW
Dubensky
Department of Immuno-Oncology, Beckman Research Institute at City of Hope, Duarte, CA 91010, USA.
Priyanka
P
Duttagupta
Department of Immuno-Oncology, Beckman Research Institute at City of Hope, Duarte, CA 91010, USA.
Marcin
M
Kortylewski
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.
Justin
J
Kline
D056704:Adaptive Immunity / Q000187:drug effects; D000818:Animals; D000938:Antigen-Presenting Cells / Q000187:drug effects / Q000378:metabolism; D000951:Antigens, Neoplasm / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005818:Genetic Engineering; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects; D007156:Immunologic Memory / Q000187:drug effects; D007370:Interferon Type I / Q000378:metabolism; D015470:Leukemia, Myeloid, Acute / Q000276:immunology* / Q000473:pathology; D008565:Membrane Proteins / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D015398:Signal Transduction / Q000187:drug effects*; D016019:Survival Analysis; D044004:Xanthones / Q000494:pharmacology; D000099197:STING Protein
D000951:Antigens, Neoplasm; D007370:Interferon Type I; D008565:Membrane Proteins; D044004:Xanthones; C530855:Sting1 protein, mouse; D000099197:STING Protein; C066668:vadimezan