Targeting early stages of cardiotoxicity from anti-PD1 immune checkpoint inhibitor therapy

Aims Cardiac immune-related adverse events (irAEs) from immune checkpoint inhibition (ICI) targeting programmed death 1 (PD1) are of growing concern. Once cardiac irAEs become clinically manifest, fatality rates are high. Cardio-oncology aims to prevent detrimental effects before manifestation of severe complications by targeting early pathological changes. We therefore aimed to investigate early consequences of PD1 inhibition for cardiac in- tegrity to prevent the development of overt cardiac disease. Methods We investigated cardiac-specific consequences from anti-PD1 therapy in a combined biochemical and in vivo pheno- and results typing approach. Mouse hearts showed broad expression of the ligand PDL1 on cardiac endothelial cells as a main mediator of immune-crosstalk. Using a novel melanoma mouse model, we assessed that anti-PD1 therapy pro- moted myocardial infiltration with CD4þ and CD8þ T cells, the latter being markedly activated. Left ventricular (LV) function was impaired during pharmacological stress, as shown by pressure–volume catheterization. This was associated with a dysregulated myocardial metabolism, including the proteome and the lipidome. Analogous to the experimental approach, in patients with metastatic melanoma (n =7) receiving anti-PD1 therapy, LV function in re- sponse to stress was impaired under therapy. Finally, we identified that blockade of tumour necrosis factor alpha (TNFa) preserved LV function without attenuating the anti-cancer efficacy of anti-PD1 therapy. Conclusions Anti-PD1 therapy induces a disruption of cardiac immune homeostasis leading to early impairment of myocardial functional integrity, with potential prognostic effects on the growing number of treated patients. Blockade of TNFa may serve as an approach to prevent the manifestation of ICI-related cardiotoxicity.