035 AIM2 regulates anti-tumor immunity from dendritic cell vaccination within the melanoma microenvironment

Successful immunotherapy strategies for melanoma must elicit the infiltration of CD8⁺ T cells into the tumor, which is mediated by the recognition of tumor-derived, cytosolic DNA by the cGAS–STING-type I interferon (IFN) signaling pathway in tumor-infiltrating dendritic cells. However, cytosolic DNA can also be recognized by AIM2, a cytosolic DNA sensor that generates IL-1β and IL-18, and also induces pyroptosis, whose function in the melanoma microenvironment remains unclear. Here we report that an intravenously injected premelanosome protein (PMEL) peptide-pulsed Aim2-deficient dendritic cell vaccine (Aim2^−/− DC-PMEL) significantly improves the efficacy of adoptive T-cell therapy (ACT) and anti-PD-1 immunotherapy in WT mice with B16F10 melanoma compared to similar treatment with the wild-type (WT) DC-PMEL. In contrast, the addition of an intratumoral injection of DNase I to ACT with Aim2^−/− DC-PMEL abrogated the phenotype, suggesting that the enhanced anti-melanoma immunity of the Aim2^−/− DC-PMEL is dependent on the recognition of tumor-derived DNA within the melanoma microenvironment. Mechanistic studies using ACT in combination with WT, Aim2^−/−, Aim2^−/−Sting^−/−, Aim2^−/−Ifnar^−/−, Aim2^−/−Cxcl10^−/−, Il-1β^−/−, or Il-18^−/− DC-PMEL revealed that the Aim2^−/− DC-PMEL enhances activation of STING-type I IFN signaling, which promotes tumor antigen-specific CD8⁺ T-cell infiltration into the tumor via CXCL10. In addition, the activation of STING-type I IFN signaling and suppression of IL-1β and IL-18 production in response to tumor-derived DNA by Aim2^−/− DC-PMEL prevent regulatory T-cell tumor infiltration. Finally, the administration of AIM2 siRNA-transfected WT DC-PMEL also improved the efficacy of ACT. Collectively, these data indicate that AIM2 is a regulator of multiple immunosuppressive signaling pathways in tumor-infiltrating DC vaccine and may be targeted to improve the efficacy of immunotherapy for melanoma.