While type-I interferons (IFN) 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 impacts 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 show increased CD11b + Gr-1 + immature myeloid suppressor and CD25 + Foxp3 + regulatory T (Treg) cells, and decreased IFNγ-producing CD8 + T cells. CD4 + and CD8 + T cells that received direct type-I IFN signals demonstrate 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) improves the survival of glioma-bearing mice associated with enhanced type-I IFN signaling, Cxcl10 and Ccl5 and T-cell migration into the brain. In a combination with subcutaneous OVA peptide-vaccination, c-di-GMP increased OVA-specific cytotoxicity of BILs and prolonged the survival. These data demonstrate significant contributions of STING to antitumor immunity via enhancement of the type-I IFN signaling in the tumor microenvironment, and suggest a potential use of STING agonists for development of effective immunotherapy, such as the combination with antigen-specific vaccinations.
CITATION STYLE
Ohkuri, T., Ghosh, A., Kosaka, A., Zhu, J., Ikeura, M., David, M., … Okada, H. (2014). STING contributes to anti-glioma immunity via triggering type-I IFN signals in the tumor microenvironment. Journal for ImmunoTherapy of Cancer, 2(Suppl 3), P228. https://doi.org/10.1186/2051-1426-2-s3-p228
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