title: Direct Activation of STING in the Tumor Microenvironment Leads to Potent and Systemic Tumor Regression and Immunity.
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.
authors.affiliation: Department of Pathology, The University of Chicago, 929 E57th Street GCIS 3H, Chicago, IL 60637, USA.
authors.forename: Leticia
authors.initials: L
authors.lastname: Corrales
authors.affiliation: Aduro BioTech, Inc., 626 Bancroft Way, 3C, Berkeley, CA 94710, USA.
authors.forename: Laura Hix
authors.initials: LH
authors.lastname: Glickman
authors.affiliation: Aduro BioTech, Inc., 626 Bancroft Way, 3C, Berkeley, CA 94710, USA.
authors.forename: Sarah M
authors.initials: SM
authors.lastname: McWhirter
authors.affiliation: Aduro BioTech, Inc., 626 Bancroft Way, 3C, Berkeley, CA 94710, USA.
authors.forename: David B
authors.initials: DB
authors.lastname: Kanne
authors.affiliation: Aduro BioTech, Inc., 626 Bancroft Way, 3C, Berkeley, CA 94710, USA.
authors.forename: Kelsey E
authors.initials: KE
authors.lastname: Sivick
authors.affiliation: Aduro BioTech, Inc., 626 Bancroft Way, 3C, Berkeley, CA 94710, USA.
authors.forename: George E
authors.initials: GE
authors.lastname: Katibah
authors.affiliation: Department of Pathology, The University of Chicago, 929 E57th Street GCIS 3H, Chicago, IL 60637, USA.
authors.forename: Seng-Ryong
authors.initials: SR
authors.lastname: Woo
authors.affiliation: Aduro BioTech, Inc., 626 Bancroft Way, 3C, Berkeley, CA 94710, USA.
authors.forename: Edward
authors.initials: E
authors.lastname: Lemmens
authors.affiliation: Aduro BioTech, Inc., 626 Bancroft Way, 3C, Berkeley, CA 94710, USA.
authors.forename: Tamara
authors.initials: T
authors.lastname: Banda
authors.affiliation: Aduro BioTech, Inc., 626 Bancroft Way, 3C, Berkeley, CA 94710, USA.
authors.forename: Justin J
authors.initials: JJ
authors.lastname: Leong
authors.affiliation: Aduro BioTech, Inc., 626 Bancroft Way, 3C, Berkeley, CA 94710, USA.
authors.forename: Ken
authors.initials: K
authors.lastname: Metchette
authors.affiliation: Aduro BioTech, Inc., 626 Bancroft Way, 3C, Berkeley, CA 94710, USA. Electronic address: tdubensky@aduro.com.
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Dubensky
authors.affiliation: Department of Pathology, The University of Chicago, 929 E57th Street GCIS 3H, Chicago, IL 60637, USA. Electronic address: tgajewsk@medicine.bsd.uchicago.edu.
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Gajewski
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D004797:Enzyme-Linked Immunosorbent Assay; D055786:Gene Knockout Techniques; D006801:Humans; D008264:Macrophages; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000276:immunology*; D009712:Nucleotides, Cyclic / Q000138:chemical synthesis / Q000494:pharmacology*; D016133:Polymerase Chain Reaction; D014162:Transfection; D059016:Tumor Microenvironment / Q000276:immunology*; D044004:Xanthones / Q000494:pharmacology; D000099197:STING Protein
chemical_list: D000970:Antineoplastic Agents; D008565:Membrane Proteins; D009712:Nucleotides, Cyclic; D044004:Xanthones; C530855:Sting1 protein, mouse; D000099197:STING Protein; C066668:vadimezan