Enhancing metabolic fitness and CAR T cell function using microRNA-29a 4225

Abstract Description Adoptive cell therapy using chimeric antigen receptor (CAR) T cells that eliminate tumor cells, has revolutionized cancer therapy for some cancer patients. However, low persistence of CAR T cells and progressive T cell exhaustion pose significant challenges for CAR T therapy. We recently demonstrated that microRNA-29a (miR-29a) attenuates T cell exhaustion and promotes long-term persistence of CD8 T cells, while retaining their effector functions. Transcriptomic analyses revealed that miR-29a-overexpressing CD8 T cells enriched for fatty acid metabolism and oxidative phosphorylation. Here, we found that miR-29a deficient CD8 cells have decreased spare respiratory capacity and mitochondrial content. Therefore, we hypothesized that miR-29a enhances CAR T responses by improving metabolic fitness. Indeed, the transcriptional profile of miR-29a-overexpressing CD8 T cells enriched for genes associated to complete CAR T cell responses. Therefore, we transduced T cells with CD19-CAR and miR-29a or only CD19-CAR. miR-29a significantly enhanced killing of tumor cells, enhanced survival and increased stemness of CAR-T cells following repetitive restimulations in vitro. Subsequently, we isolated RNA from pre-infusion CAR-T leukapheresis products of DLBCL patients and found that miR-29a expression correlated with clinical responses. Thus, we suggest miR-29a as a novel strategy to enhance CAR T cell responses and promote the benefits of immunotherapy. Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)