STING contributes to antiglioma immunity via triggering type I IFN signals in the tumor microenvironment

• Published in: Cancer immunology research 2014-12, Vol.2 (12), p.1199-1208
• Main Authors: Ohkuri, Takayuki, Ghosh, Arundhati, Kosaka, Akemi, Zhu, Jianzhong, Ikeura, Maki, David, Michael, Watkins, Simon C, Sarkar, Saumendra N, Okada, Hideho
• Format: Article
• Language: English
• Subjects: Animals; Cancer Vaccines - immunology; CD11b Antigen - metabolism; CD11c Antigen - metabolism; Cell Line, Tumor; Cyclic GMP - analogs & derivatives; Cyclic GMP - pharmacology; Disease Models, Animal; Gene Expression Profiling; Glioma - genetics; Glioma - immunology; Glioma - metabolism; Glioma - mortality; Interferon Type I - metabolism; Membrane Proteins - agonists; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice; Mice, Knockout; Signal Transduction - immunology; T-Lymphocyte Subsets - immunology; T-Lymphocyte Subsets - metabolism; Tumor Microenvironment - immunology
• ISSN: 2326-6066; 2326-6074
• DOI: 10.1158/2326-6066.CIR-14-0099

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.