Monday, April 29, 2024
4/29/2024
Project Summary Cardiovascular disease is the leading cause of death worldwide and despite efforts to preserve cardiac function in heart failure patients, preventing adverse remodeling and fibrosis remains a challenging task. Cardiac fibrosis can negatively impact cardiac compliance and function, and is associated with worsened outcomes in heart failure patients. Recent sequencing technology advancements hav e allowed for the identification of fibroblast activation protein (FAP) as a marker of pathologically activated fibroblasts present in failing hearts but not in healthy controls. This has raised the possibility of selectively depleting FAP+ cells for heart failure therapy. One proposed strategy is to use chimeric antigen receptor (CAR) T cells that are engineered to express a surface receptor directed against FAP. Initial studies utilizing these FAP CAR T cells in a mouse model of hypertensive cardiac injury have been promising, but the effects of CAR T cells on the myocardial environment are not understood. The proposed project aims to investigate the feasibility of T cell engaging therapies as a strategy of targeted cell depletion in cardiac fibrosis, and also investigate the modes of crosstalk between FAP CAR T cells and other cell populations in the heart. These questions have broad implications for this novel cardiac application of cellular immunotherapy. Preliminary data demonstrate that FAP CAR T cells can actually worsen the development of fibrosis in an angiotensin II/phenylephrine mouse model of cardiac injury. Importantly, expression of interferon gamma (IFN¿) and its targets is elevated in the hearts of FAP CAR T cell treated mice compared to those of control T cell treated mice. IFN¿ has been shown to worsen fibrosis in other models of cardiac injury. We hypothesize that FAP CAR T cells can deplete activated fibroblasts, and that this has an anti-fibrotic effect, but it is offset by pro-inflammatory, pro-fibrotic crosstalk between FAP CAR T cells and other immune cells in the myocardium. Aim 1 of this proposal focuses on delineating the feasibility of T cell engaging therapies in cardiac fibrosis. Specifically, it compares FAP CAR T cells to other T cell-based therapies such as bispecific T cell engagers (BiTE®) in target cell depletion, IFN¿ activation, and fibrosis modulation. Aim 2 studies how blocking IFN¿ signaling in FAP CAR T cell treated mice affects the cellular and transcriptional landscape of the heart. It also investigates which cells are the sources of IFN¿, which cells are responding to this signal during FAP CAR T cell treatment, and what effects these signaling axes have on myocardial inflammation and fibrosis. Together these aims seek to understand the effects and mechanisms of FAP CAR T cell cross talk with other myocardial immune populations, and can potentially inform the field of strategies to refine T cell engaging therapies to maximize efficacy and improve safety in the cardiac setting.
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