MicroRNA regulation of messenger RNA vaccine responses in a mouse model of acute myeloid leukemia 3050

Abstract Description Acute myeloid leukemia (AML) is the most common adult leukemia and is characterized by aggressive myeloblast proliferation. CAR-T cell and immune checkpoint blockade immunotherapies are in clinical trials for their ability to enhance durable anti-AML immune responses, but have yielded mixed results. MicroRNAs in immune cells act as critical regulatory elements for anti-tumor immunity and response to immunotherapies through posttranscriptional repression of dose-sensitive target genes. Chief among these is microRNA-155 (miR-155), which plays a key role in determining CD4+ and CD8+ T cell states. We describe a novel role for miR-155 as necessary for the response to a tumor-specific messenger RNA (mRNA) vaccine strategy eliciting selective T cell responses against murine C1498-OVA AML. In vitro, we show dendritic cells receiving mRNA-lipid nanoparticle complexes activate WT OT-1 and OT-2 cells, yet this response is defective upon deletion of miR-155 in these T cell types. In vivo, we use miR-155fl/fl CD4+Cre T cell conditional knockout mice (miR-155 TCKO) to show that T cell miR-155 is necessary for the induction of sterilizing immunity to murine AML. Single-cell RNA sequencing reveals that WT mice receiving tumor-specific mRNA exhibit expansion of Cx3Cr1+ and KLRG1+ CD8+ T cells as compared to their miR-155 TCKO counterparts. Together, these data suggest T cell miR-155 is crucial for selective cytotoxic responses to tumor-specific mRNA vaccine immunotherapies. Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)