STING Contributes to Antiglioma Immunity via Triggering Type I IFN Signals in the Tumor Microenvironment

Abstract

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 StingGt/Gt mice showed shorter survival, and lower expression levels of Ifns compared with wild-type mice. Furthermore, BILs of StingGt/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.

The host STING pathway at the interface of cancer and immunity

“…Persistent activation of STAT3 was associated with amplified inflammation and promotion of colon tumorigenesis (61). In an inducible model of glioma generated using a sleeping beauty transposon system, animals with a mutation rendering STING nonfunctional (I199N) (62) produced lower levels of type I IFNs, mainly generated by brain-infiltrating CD11b + cells, which correlated with reduced immune-mediated tumor control (63). In transplantable models of melanoma and lymphoma, activation of the STING pathway in CD11c + cells after cryoablation has been reported to lead to the production of type I IFNs and generation of an adaptive immune response against tumor-associated antigens (64).…”

“…STING-activating CDNs may have high translational potential as oncology therapeutics due to their potent antitumor activity as a single agent in aggressive mouse syngeneic tumor models (8,63,(83)(84)(85)(86). Therapeutic antitumor efficacy with CDN-based STING agonists was initially demonstrated with daily i.p.…”

Innate immune signaling and regulation in cancer immunotherapy

“…However, mice lacking the adaptor molecule stimulator of interferon genes (STING, also known as TMEM173, MITA, ERIS, and MPYS) or the transcription factor IRF3, which is activated downstream of STING stimulation, showed blunted anti-tumor T cell priming and deficient rejection of transplantable tumors [45,53]. The host STING pathway has also been shown to be protective in other tumor models, including in a mouse model of colitis-associated carcinogenesis induced by azoxymethane/ dextran sodium sulfate [54][55][56] and in a glioma model caused by a sleeping beauty transposon system [57].…”

Ecrg4 contributes to the anti-glioma immunosurveillance through type-I interferon signaling

“…34 Briefly, brain tissues were mechanically minced, resuspended in 70% Percoll (GE), overlaid with 37% and 30% Percoll, and centrifuged for 20 min at 500 £ g.…”