Metabolomic and Genetic Factors Decoupling Immune Checkpoint Inhibitor Tumor Efficacy and Cardiovascular Toxicity

PROJECT SUMMARY/ABSTRACT Immune checkpoint inhibitors (ICIs) are an important advancement in oncology and have restored anti-tumor immune responses, resulting in improved survival in many cancer types. Nevertheless, there is emerging evidence that ICIs are associated with cardiovascular toxicities, including myocarditis, which has mortality rates as high as 50% in fulminant cases. Additionally, ICIs are associated with excess atherosclerotic events, such as myocardial infarction, stroke, and peripheral artery disease. Apart from toxicities associated with ICIs, there is a small group of patients who are non-responders to ICIs; many recent studies suggest that ICIs may induce various forms of immune dysregulation, which may paradoxically accelerate cardiovascular disease (CVD). Immune dysregulation is largely defined by increased oxidative stress, accumulation of reactive oxygen species (ROS), and immune cell senescence. Senescent immune cells demonstrate limited surveillance of immune responses, but also become pro-inflammatory due to a permanent change in gene expression profile termed a senescence-associated secretory phenotype (SASP), that can induce chronic inflammation, tissue damage, resist immunotherapy, and progress CVD. Based on these observations, we hypothesize that immuno- senescence is a central linking mechanism of ICI-associated cardiovascular disease (ICI-CVD) and ultimately length of survival in cancer patients. Importantly, our preliminary work suggests that immuno-senescence that preexisted prior to treatment, rather than toxicity that developed during treatment, drives cardiovascular risk and negatively impacts cancer treatment effect. For example, we found that metabolomic measures and epigenetics prior to ICI treatment predicts the development of cardiovascular events of post-ICI treatment, highlighting the value of evaluating baseline immune health prior to treatment. In order to address this clinical question, our project is a paradigm shift by combining clinical data with multi-omics biosample-derived biomarkers before and after ICI treatment, such as metabolomics, aging through epigenetic markers, and clonal hematopoiesis of indeterminate potential (CHIP), to develop predictive models that differentiate patients according to their estimated risk of ICI-CVD and cancer mortality. This systems-level approach utilizes three aims: (1) discouple the biological predictors of cardiovascular toxicity from ICI efficacy; (2) identify metabolite patterns of human monocyte-derived macrophages (HMDMs) that are associated with cardiovascular and oncologic outcomes; and (3) identify genetic and epigenetic determinants, including CHIP, of cardiovascular risk and cancer prognosis in patients receiving ICI therapy. Using this integrated strategy we aim to address clinical management by providing biomarkers that predict both subsequent cardiovascular event incidence and poor cancer outcomes. Our findings may help us determine new therapeutic interventions that separate the anti-tumor benefit of ICI from their cardiovascular risks. Moreover, we will be able to refine diagnostic criteria, and develop a grading scale for ICI- CVD that may help improve clinical decision-making in relation to continuing treatment, and ultimately improve survival, and quality of life for cancer patients receiving immunotherapy.