Direct Activation of STING in the Tumor Microenvironment Leads to Potent and Systemic Tumor Regression and Immunity
| Autor: | Sarah M. McWhirter, Seng-Ryong Woo, Ken Metchette, Justin Leong, Edward E. Lemmens, George E. Katibah, Tamara Banda, David B. Kanne, Thomas F. Gajewski, Leticia Corrales, Thomas W. Dubensky, Laura Hix Glickman, Kelsey E. Sivick |
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| Rok vydání: | 2015 |
| Předmět: |
Agonist
medicine.drug_class Xanthones T cell Blotting Western Priming (immunology) Antineoplastic Agents Enzyme-Linked Immunosorbent Assay Transfection Polymerase Chain Reaction Article General Biochemistry Genetics and Molecular Biology Gene Knockout Techniques Mice Immune system Immunity Cell Line Tumor Tumor Microenvironment Animals Humans Medicine lcsh:QH301-705.5 Mice Inbred BALB C Tumor microenvironment business.industry Macrophages Membrane Proteins Neoplasms Experimental eye diseases 3. Good health Mice Inbred C57BL Sting medicine.anatomical_structure lcsh:Biology (General) Stimulator of interferon genes Immunology Nucleotides Cyclic business |
| Zdroj: | Cell Reports, Vol 11, Iss 7, Pp 1018-1030 (2015) |
| ISSN: | 2211-1247 |
| Popis: | SummarySpontaneous 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. |
| Databáze: | OpenAIRE |
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