1324 Local Delivery of Type 1 Interferon-Stimulating Agent Within Tumor Microenvironment Promotes Dendritic Cell Antigen Presentation and T Cell Activation in Glioblastoma

INTRODUCTION: While immunotherapy has demonstrated efficacy in many cancer types, glioblastoma (GBM) is known to have a “cold”, immunosuppressive tumor microenvironment (TME). Stimulator of Interferon Genes (STING) is thought to be a general myeloid cell reactivator, yet it is unclear how STING can activate myeloid and downstream lymphoid cells in GBM. METHODS: Mice orthotopically implanted with GL261-luciferase glioma cells were intracranially injected with 1ug STING (2’,3’-cGAMP) 10 days after tumor implantation. Ex vivo flow cytometry was used to analyze DC subpopulations and T cell activation. Interferon-G ELISA was used to assess the ability of ex vivo DCs to activate T cells. DQ-ovalbumin assays were used to assess antigen presentation. Kaplan-Meier curves were generated to assess the impact of STING on overall survival (OS). RESULTS: Mice treated with intracranial STING produced increased DCs with enhanced ability to activate T cells. This was associated with increased trafficking of CD69+ activated T cells in the TME. Dendritic cells in the draining lymph nodes broadly demonstrated increased phagocytosis ability, while classical DCs type 1 (cDC1s) and plasmacytoid DCs (pDCs) showed increased antigen-presentation ability, as shown by DQ-ovalbumin signaling in these lymph nodes. Intracranial STING-treated mice also showed significantly increased OS when compared to sham-treated mice. CONCLUSIONS: Our findings demonstrate preclinical efficacy of STING agonist delivered locally to enhance immune activation in the brain and tumor-draining lymph nodes in a GBM model. cDC1s and pDCs are activated in the draining lymph nodes, increasing cytotoxic T cell trafficking to and activation in the TME. Given enhanced OS, these findings provide rationale for activating antigen presentation in these DC populations to generate an antitumor immune response.