title: STING contributes to antiglioma immunity via triggering type I IFN signals in the tumor microenvironment.
abstract: Although type I IFNs play critical roles in antiviral and antitumor activity, it remains to be elucidated how type I IFNs are produced in sterile conditions of the tumor microenvironment and directly affect tumor-infiltrating immune cells. Mouse de novo gliomas show increased expression of type I IFN messages, and in mice, CD11b(+) brain-infiltrating leukocytes (BIL) are the main source of type I IFNs that are induced partially in a STING (stimulator of IFN genes)-dependent manner. Consequently, glioma-bearing Sting(Gt) (/Gt) mice showed shorter survival and lower expression levels of Ifns compared with wild-type mice. Furthermore, BILs of Sting(Gt) (/Gt) mice showed increased CD11b(+) Gr-1(+) immature myeloid suppressor and CD25(+) Foxp3(+) regulatory T cells (Treg) and decreased IFNγ-producing CD8(+) T cells. CD4(+) and CD8(+) T cells that received direct type I IFN signals showed lesser degrees of regulatory activity and increased levels of antitumor activity, respectively. Finally, intratumoral administration of a STING agonist (cyclic diguanylate monophosphate; c-di-GMP) improved the survival of glioma-bearing mice associated with enhanced type I IFN signaling, Cxcl10 and Ccl5, and T-cell migration into the brain. In combination with subcutaneous OVA peptide vaccination, c-di-GMP increased OVA-specific cytotoxicity of BILs and prolonged their survival. These data demonstrate significant contributions of STING to antitumor immunity via enhancement of type I IFN signaling in the tumor microenvironment and suggest a potential use of STING agonists for the development of effective immunotherapy, such as the combination with antigen-specific vaccinations.
authors.affiliation: Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania. Department of Brain Tumor, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Ohkuri
authors.affiliation: Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania. Cancer Virology Programs, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania.
authors.forename: Arundhati
authors.initials: A
authors.lastname: Ghosh
authors.affiliation: Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania. Department of Brain Tumor, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania.
authors.forename: Akemi
authors.initials: A
authors.lastname: Kosaka
authors.affiliation: Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania. Cancer Virology Programs, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania.
authors.forename: Jianzhong
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Department of Brain Tumor, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania.
authors.forename: Maki
authors.initials: M
authors.lastname: Ikeura
authors.affiliation: Division of Biology, University of California San Diego, La Jolla, California.
authors.forename: Michael
authors.initials: M
authors.lastname: David
authors.affiliation: Department of Cell Biology and Physiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors.forename: Simon C
authors.initials: SC
authors.lastname: Watkins
authors.affiliation: Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania. Cancer Virology Programs, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania. Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania. saumen@pitt.edu OkadaH@neurosurg.ucsf.edu.
authors.forename: Saumendra N
authors.initials: SN
authors.lastname: Sarkar
authors.affiliation: Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania. Department of Brain Tumor, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania. Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania. Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania. Department of Cancer Immunology, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania. saumen@pitt.edu OkadaH@neurosurg.ucsf.edu.
authors.forename: Hideho
authors.initials: H
authors.lastname: Okada
mesh_terms: D000818:Animals; D039481:CD11b Antigen / Q000378:metabolism; D039521:CD11c Antigen / Q000378:metabolism; D019496:Cancer Vaccines / Q000276:immunology; D045744:Cell Line, Tumor; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000494:pharmacology; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D005910:Glioma / Q000235:genetics / Q000276:immunology* / Q000378:metabolism* / Q000401:mortality; D007370:Interferon Type I / Q000378:metabolism*; D008565:Membrane Proteins / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D015398:Signal Transduction / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D059016:Tumor Microenvironment / Q000276:immunology*; D000099197:STING Protein
chemical_list: D039481:CD11b Antigen; D039521:CD11c Antigen; D019496:Cancer Vaccines; D006152:Cyclic GMP; D007370:Interferon Type I; D008565:Membrane Proteins; C530855:Sting1 protein, mouse; D000099197:STING Protein; C062025:bis(3',5')-cyclic diguanylic acid