IFN-γ activates the tumor cell-intrinsic STING pathway through the induction of DNA damage and cytosolic dsDNA formation

Abstract

Stimulator of interferon genes (STING) pathway activation predicts the effectiveness of targeting the PD-1/PD-L1 axis in lung cancer. Active IFN-γ signaling is a common feature in tumors that respond to PD-1/PD-L1 blockade. The connection between IFN-γ and STING signaling in cancer cells has not been documented. We showed that IFN-γ caused DNA damage and the accumulation of cytosolic dsDNA, leading to the activation of the cGAS- and IFI16-dependent STING pathway in lung adenocarcinoma cells. IFN-γ-induced iNOS expression and nitric oxide production were responsible for DNA damage and STING activation. Additional etoposide treatment enhanced IFN-γ-induced IFN-β and CCL5 expression. Tumor-infiltrating T cells stimulated with a combination of anti-CD3 and anti-PD-1 antibodies caused STING activation and increased IFN-β and CCL5 expression in lung adenocarcinoma. These effects were abrogated by the addition of an IFN-γ neutralizing antibody. Our results suggest that the activation of tumor-infiltrating T cells could alter the tumor microenvironment via the IFN-γ-mediated activation of STING signaling in cancer cells.

Anti-Inflammatory Effects of Red Rice Bran Extract Ameliorate Type I Interferon Production via STING Pathway

“…In addition, activation through the STING pathway enhances IFNs-I. Then, these cytokines initiate IFN-γ secretion [ 30 ], which increases the expression of iNOS and leads to nitric oxide (NO) production in activated macrophages [ 31 ]. Our study at 24 h showed that the secretion of IFN-γ and nitric oxide (NO) from DMXAA activation in the culture medium significantly increased ( Figure 4 A,B), while the mRNA levels of Ifn-γ, Ifn-α, and Ifn-β were downregulated in the presence of RRBE ( Figure 4 C–E).…”

“…This data may result from the decrease in IFN-γ secretion and type I IFNs (IFN-α and IFN-β) in the supernatant, which can turn on the expression of Cxcl10 via activating the JAK/STAT pathway [ 44 , 45 , 46 ]. Moreover, the secretion of IFN-γ (after binding their receptors) can initiate the transcription of inducible nitric oxide synthase (iNOS) in activated macrophages [ 47 ] through the induced tyrosine phosphorylation of STAT1 signaling [ 48 ], and promote the production of NO ( Figure 4 B) [ 31 , 49 , 50 ]. These data suggested that RRBE reduced the IFN-γ and nitric oxide was STING-dependent.…”

Epigenetically suppressed tumor cell intrinsic STING promotes tumor immune escape

“…In tumors, cytosolic dsDNA can be induced by IFN-γ, a common tumor feature, and then activates the STING pathway in cancer cells [ 22 ]. The activation of STING leads to phosphorylation of IRF3 and secretion of type-I interferons, e.g.…”

“…Several studies have shown that suppression of the STING pathway in tumor cells contributed to immune evasion [ 30 , 32 - 36 ]. In addition, tumor intrinsic STING and its induced immune response are required for the efficacy of 5-Fluorouracil, a chemotherapeutic drug [ 37 ], immune checkpoint blockade [ 22 ], and oncolytic viruses [ 14 ]. Mechanistically, the STING pathway is found to be silenced by major oncogenic drivers, e.g.…”

T-cell derived extracellular vesicles prime macrophages for improved STING based cancer immunotherapy

“…Our finding indicated that both IFNγ and TNFα was primarily surface bound, as blocking their designated receptors on macrophages prohibited the sensizatiation of the STING pathway. Multiple studies have described that tumors responding to ICI can be associated with active IFNγ signaling [51,52], and the effect of IFNγ is associated with modulation of cancer cells and their activation of the STING pathway by increasing DNA damage and cGAMP production [53][54][55]. In parallel, IFNγ is also essential in activating and inducing a proinflammatory phenotype in macrophages [56][57][58].…”