Abstract A173: Inhibition of the STING pathway by the AIM2 inflammasome

Abstract

Abstract Recognition of tumor-derived DNA by the cGAS/STING pathway in the cytosol of antigen-presenting cells leads to production of type I IFN, facilitating adaptive immunity against tumors. But cytosolic DNA is also recognized by AIM2, leading to the assembly of the AIM2 inflammasome and the production of mature IL-1 and IL-18. As stimulation of the STING pathway by endogenous tumor-derived DNA or exogenous therapeutic agonists have shown to trigger an immune response against tumors, a key question was whether the AIM2 inflammasome would have a positive or negative regulatory role, given the sharing of the same ligand by both pathways. In vivo, sorted CD45+ cells from implanted B16 tumors in AIM2-/- animals showed a higher IFN-β expression than the same cells sorted from WT mice, suggesting that AIM2 plays a negative role in the induction of type I IFN in vivo. Experiments in vitro confirmed that macrophages and dendritic cells from AIM2-, ASC-, or caspase-1-deficient mice produced substantially higher IFN-β in response to tumor-derived DNA. Biochemical analysis revealed that all steps in the STING pathway were enhanced in the inflammasome deficient cells: generation of cGAMP, aggregation of STING, and phosphorylation of TBK1 and IRF3. Studies investigating the biological mechanism by which activation of the AIM2 inflammasome inhibits the STING pathway revealed that pyroptosis induced by activation of the AIM2 inflammasome was critically involved. Pre-incubation with a caspase-1 inhibitor abolished cell death, and recovered a significant proportion of phosphorylation of TBK1/IRF3 and production of IFN-β. Our data suggest that the activation of AIM2 inflammasome inhibits the STING pathway mainly by cell death derived from the activation of the inflammasome. This crosstalk may have potential consequences for anti-tumor immunity which should be explored in vivo. Citation Format: Leticia Corrales, Seng-Ryong Woo, Thomas F. Gajewski. Inhibition of the STING pathway by the AIM2 inflammasome. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A173.