Monday, April 29, 2024
4/29/2024
Project Summary/Abstract (30 lines) Immunotherapy has revolutionized cancer treatment and is a cornerstone of standard clinical practice and ongoing clinical trials. However, some immunotherapies including immune checkpoint inhibitors (ICIs) impart adverse cardiac events ranging from arrhythmias to fulminant myocarditis. While the mechanistic basis for adverse cardiac events from cancer therapies targeting immune checkpoints is not known, recent evidence suggests that macrophage infiltration and aberrant T-cell activation may be contributing factors. Ligand-receptor interactions between antigen presenting cells (APCs) and T-cells comprise current targets for immunotherapy. When used in combination with ICIs, CD40 agonists increase efficacy against previously untreatable tumors. CD40 signaling mediates activation of macrophages to heighten downstream T-cell responses. CD40 is primarily expressed on APCs such as macrophages, and its ligand is expressed on T- cells. Little is known regarding how CD40 agonists impact the heart including the potential for adverse cardiac events. The principal investigator (PI) has established that CD40 agonist treatment activates an inflammatory response in the heart that may lead to injury. In this proposal, the PI will test the hypothesis that CD40 signaling alters the immune landscape of the heart, priming the inflammatory response to myocardial injury. The scientific goals of this proposal are focused on identifying mechanisms of cardiac injury and remodeling as a result of cancer immunotherapies that regulate immune checkpoints, which may be targeted to improve clinical outcomes. The PI plans to investigate the immune cell target(s) of CD40 signaling (Aim 1), the key regulators and mechanism of signaling (Aim 2), and the effect the inflammatory response has on cardiac remodeling (Aim 3). Completion of these aims will allow the PI to gain technical expertise in flow cytometry, single cell sequencing, immune functional assays, and evaluation of cardiac injury and cancer models. The career development goals of this proposal are focused on developing the PI into an independent physician scientist in the field of cardiovascular research. The PI is an MD/PhD with advanced training in basic and translational cardiovascular research during his post-doctoral fellowship and has completed clinical training in Internal Medicine, Cardiovascular Diseases, and Cardio-Oncology. Within the next 5 years, the PI plans to: 1) develop collaborative relationships with his mentoring committee; 2) develop core and advanced competencies in bioinformatics with a focus on single cell sequencing analysis, and in immunology with a focus on cardiac immunology and immunotherapies; 3) strengthen grant writing, manuscript preparation, data presentation, and mentoring skills. At the conclusion of this mentored clinical scientist training proposal, the PI will have acquired mentorship, technical, didactic, and professional development training to become an independent and successful physician scientist.
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