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- W4313366247 abstract "Abstract BACKGROUND In situ vaccination (ISV) against lymphoma can be achieved with Flt3-ligand treatment to recruit dendritic cells (DC), radiotherapy to load DC with tumor antigens, and intratumoral injection of a pattern-recognition- receptor agonist (PRRa) to activate antigen-loaded DC. While clinical trials of ISV using synthetic PRRa have yielded remissions, the optimal approach to activate DC is unknown. We hypothesize that ‘natural’ PRRa, such as the attenuated pathogens in common prophylactic vaccines, could target multiple PRR, leading to more robust activation of DC as compared to synthetic PRRa. METHODS 20 FDA-approved vaccines (BCG, MMR, etc.) were screened in vitro, for their effect on DC phenotype and function. DC tumor antigen cross-presentation was assessed using CRISPR gene-edited β2m−/−GFP-lymphoma cells and a GFP-specific CD8 T cell system. Mechanisms of immune activation were interrogated using MyD88, TRIF, MAVS, and IFNAR knockout mice, as well as a library of CRISPR-edited PRR-null Raw264 macrophages. Potent vaccines functioning through distinct mechanisms were evaluated in vivo in an ISV using the A20 murine lymphoma model. RESULTS Several vaccines induced robust DC activation, cross-presentation and increases in T cell activation, proliferation, and tumor killing. Some vaccines were more effective than synthetic PRRa in activating DCs to induce a T cell response. Distinct PRR and signaling pathways were engaged by different vaccines. In vivo, vaccine combination therapy induced tumor regression in a majority of animals. CONCLUSIONS Prophylactic vaccines, used alone or in combination, are effective DC activators and can be repurposed for use in ISV, with immediate translation into the clinic." @default.
- W4313366247 created "2023-01-06" @default.
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- W4313366247 date "2019-05-01" @default.
- W4313366247 modified "2023-09-26" @default.
- W4313366247 title "Natural Adjuvants for <i>in situ</i> Vaccination Lymphoma Immunotherapy" @default.
- W4313366247 doi "https://doi.org/10.4049/jimmunol.202.supp.70.9" @default.
- W4313366247 hasPublicationYear "2019" @default.
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