Abstract B12: T-cell derived extracellular vesicles prime macrophages for improved STING based cancer immunotherapy


 Despite recent years advancement reported for cancer immunotherapies within multiple cancer types, we still see a large group of patients failing to respond to treatment. Activation of the innate immune pathway controlled by STimulator of INterferon Genes (STING) has been considered as an attractive target for boosting cancer immunotherapy. Extracellular vesicles (EVs) are key players in shaping immune responses and are proposed to provide a danger signal for antigen-presenting cells. Here, we hypothesize that CD4+ T-cell derived EVs (T-EVs) enhance innate immune cells function, such as macrophages, by priming the STING signaling pathway. We purified T-EVs from aCD3/aCD28 stimulated CD4+ T cells by differential ultracentrifugation, and primed macrophages with these prior to stimulation with STING agonists. Subsequent activation was measured by induction of type I Interferons and phosphorylation of signaling molecules within the STING pathway. We further explored the in vivo efficacy of combining T-EVs priming and STING agonists in tumor bearing mice models. We found that T-EVs sensitizes macrophages to respond more potently to STING activation. Importantly, this was independent on both surface-associated and intravesicular DNA. The priming of STING signaling was largely induced by IFNγ and TNFα carried by the T-EVs. We further showed that the T-EVs enhances the efficacy of STING agonist stimulation, by controlling tumor growth in syngeneic MC38 tumor models. Our work support that T-EVs can disrupt the immune suppressive tumor microenvironment by reprogramming macrophages to a pro-inflammatory phenotype, and priming them for a robust immune response towards STING activation.
 Citation Format: Aida S. Hansen, Lea S. Jensen, Kristoffer G. Ryttersgaard, Christian Krapp, Jesper Just, Kasper L. Joensson, Anders Etzerodt, Bent W. Deleuran, Martin R. Jakobsen. T-cell derived extracellular vesicles prime macrophages for improved STING based cancer immunotherapy [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy; 2022 Oct 21-24; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(12 Suppl):Abstract nr B12.