====== Stimulator of interferon genes (STING) ======

[[Stress]] conditions such as UV irradiation, exposure to genotoxic agents, stalled [[DNA replication]], and even tumors trigger the release of cytosolic genomic DNA (cgDNA). Classically, cgDNA induces interferon response via its binding to proteins such as [[STING]].
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STING contributes to antiglioma immunity by triggering type I [[interferon]] (IFN) induction in [[glioma]] microenvironment. Moreover, intratumoral administration of STING agonist improved the efficacy of peptide vaccination in a mouse glioma model, suggesting the rational use of STING agonists in the immunotherapy of [[brain tumor]]
((Ohkuri T, Ghosh A, Kosaka A, Sarkar SN, Okada H. Protective role of STING
against gliomagenesis: Rational use of STING agonist in anti-glioma
immunotherapy. Oncoimmunology. 2015 Jan 22;4(4):e999523. eCollection 2015 Apr.
PubMed PMID: 26137417.
)).

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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
((Ohkuri T, Ghosh A, Kosaka A, Zhu J, Ikeura M, David M, Watkins SC, Sarkar SN, 
Okada H. STING contributes to antiglioma immunity via triggering type I IFN
signals in the tumor microenvironment. Cancer Immunol Res. 2014
Dec;2(12):1199-208. doi: 10.1158/2326-6066.CIR-14-0099. Epub 2014 Oct 9. PubMed
PMID: 25300859; PubMed Central PMCID: PMC4258479.
)).
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Human and mouse breast and lung cancer cells express [[protocadherin 7]] (PCDH7), which promotes the assembly of carcinoma-astrocyte gap junctions composed of [[connexin 43]] (Cx43). Once engaged with the astrocyte gap-junctional network, brain metastatic cancer cells use these channels to transfer the second messenger [[cGAMP]] to astrocytes, activating the [[STING]] pathway and production of inflammatory cytokines such as interferon-α (IFNα) and [[tumor necrosis factor]] (TNF). As paracrine signals, these factors activate the STAT1 and NF-κB pathways in brain metastatic cells, thereby supporting tumour growth and chemoresistance. The orally bioavailable modulators of gap junctions [[meclofenamate]] and [[tonabersat]] break this paracrine loop, and provide proof-of-principle that these drugs could be used to treat established brain metastasis
((Chen Q, Boire A, Jin X, Valiente M, Er EE, Lopez-Soto A, Jacob LS, Patwa R,
Shah H, Xu K, Cross JR, Massagué J. Carcinoma-astrocyte gap junctions promote
brain metastasis by cGAMP transfer. Nature. 2016 May 18;533(7604):493-8. doi:
10.1038/nature18268. PubMed PMID: 27225120; PubMed Central PMCID: PMC5021195.
)).