Inflammation and immune checkpoint inhibitors: double-edged swords at the intersection of cancer therapies, cardio-oncology and cardiovascular disease

Immune checkpoint inhibitors (ICIs) are the most widely used immunotherapy in oncology. However, they accentuate systemic inflammation which can cause cardiovascular toxicity, ranging from acute fulminant myocarditis to late-onset atherosclerosis and chronic heart failure. The rapid expansion of novel ICIs and the increased use of combination therapy means that a better understanding of the mechanisms underlying chronic cardiovascular toxicity is critically needed. Immune checkpoint proteins are expressed by cells of the immune and cardiovascular systems, highlighting the requirement to explore the effect of ICI therapy on both immune and cardiovascular cells. Remodelling of immunometabolism and epigenetic regulation are key drivers of cardiovascular disease, but the role of these processes in ICI-related toxicity is unknown, despite an established interplay between immune checkpoint signalling and immunometabolism. By combining mouse models of ICI therapy with mass cytometry, single-cell approaches, metabolite mass spectrometry, epigenomics, transcriptomics and in-vivo physiology, I will characterise the immune cell heterogeneity in cardiovascular tissues and identify the cellular and molecular drivers of ICI-associated atherosclerosis and cardiac dysfunction. Validation of findings will be undertaken in patient blood samples from a cardio-oncology biobank. This Immediate Fellowship will provide much-needed insights into the pathophysiology of late-onset ICI-related cardiovascular toxicity.