Project Summary/Abstract In this proposal, we will study the long-term cardiovascular sequelae of immune checkpoint inhibitors (ICI), therapies that have revolutionized cancer treatment. We will use both mouse models and cancer survivors treated with ICI. We have defined acute, T cell mediated cardiac complications of ICI, including myocarditis, pericarditis, and vasculitis as a significant clinical concern in these patients. Our preliminary data suggest a role for programmed death-1/ligand-1 (PD-1/PD-L1) in preventing myocardial injury and other cardiovascular disease. Clinically, we have observed patients with subacute cardiac injury following ICI treatment. We hypothesize that PD-1/PD-L1 blockade through ICI therapy, in conjunction with other cardiac insults, worsens long-term cardiovascular health. To address this, we will first utilize two mouse models that we have developed that recapitulate ICI-cardiopulmonary toxicities: a model (MRL/MpJ) treated with combination ICI therapy, and a genetic knockout model (PD1-/-; CTLA+/-). In Aim 1, we will test the hypothesis that cardiac ischemia potentiates increased immune infiltration and inflammation in our pharmacologic and genetic mouse models (compared to appropriate controls), performing in-depth physiologic and immune profiling in these mouse models. We leverage these mechanistic and pre-clinical models with translational endpoints for Aim 2, where we will utilize a large retrospective cohort of long-term survivors treated with ICI (200 patients) to assess the impact of ICI on cardiac risk factors, including blood pressure, weight, body composition, and coronary artery calcification. A prospective cohort (150 patients) will be accrued for longitudinal clinical phenotyping to identify and validate clinical endpoints and to extend and validate these findings. We will perform intensive cardiac (echocardiography, cardiac MRI, high-sensitivity troponin, C-reactive protein) and metabolic (fasting lipids and glucose) monitoring, specifically testing the hypothesis that troponin elevation early in treatment with ICI correlates with ventricular remodeling, inflammation, and fibrosis. In patients who die following recovery from myocarditis, we will perform rapid autopsies to determine the extent of inflammation, fibrosis, structural changes, and residual immune cell populations. The overwhelming success of ICI has led to a dramatic increase of long-term survivors treated with these agents. This proposal will allow us to characterize the effects of ICI on long-term cardiovascular health, thus enabling development of appropriate screening, treatment, and prevention strategies.