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

Abstract

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 integrity to prevent the development of overt cardiac disease. Methods and results We investigated cardiac-specific consequences from anti-PD1 therapy in a combined biochemical and in vivo phenotyping 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 promoted myocardial infiltration with CD4+ and CD8+ 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 response to stress was impaired under therapy. Finally, we identified that blockade of tumour necrosis factor alpha (TNFα) 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 TNFα may serve as an approach to prevent the manifestation of ICI-related cardiotoxicity.

A Systematic Review of the Mechanisms Involved in Immune Checkpoint Inhibitors Cardiotoxicity and Challenges to Improve Clinical Safety

“…These characteristics are also presented in 2 cases of ICI-related myocarditis demonstrating the ICI-induced autoimmunity ( Bockstahler et al, 2020 ). The study published by Michel et al (2022) reported a murine model on which anti-PD1 therapy promotes myocardial infiltration (CD4 + and markedly activated CD8 + T cells) and impaired left ventricular (LV) function. The analogous results of impaired LV function were found in patients with metastatic melanoma receiving anti-PD1 therapy.…”

“…The analogous results of impaired LV function were found in patients with metastatic melanoma receiving anti-PD1 therapy. Remarkably, they found that the blockade of TNFα preserved the LV function without attenuating the anti-cancer efficacy of anti-PD1 therapy ( Michel et al, 2022 ). Finally, the study of Finke et al (2021) found leukocytic infiltration (CD3 + and CD8 + cells) in cardiac biopsies from patients with ICI-associated myocarditis and the upregulation of IFN-ƴ pathway, which may indicate a possible link to the inflammasome activation and M1 macrophages activity( Fujiwara et al, 2016 ).…”

Holistic Approach to Immune Checkpoint Inhibitor-Related Adverse Events

“…Recent experimental data point to the hypothesis that anti-PD-1 therapy induces a smouldering disruption of cardiac immunity towards an inflammatory phenotype, with manifest consequences on cardiac function in the presence of a second hit, in the form of systemic stress induced by presence of a tumor ( 199 ). This also indicates the possibility that the inflammatory phenotype raises the risk for the development of myocarditis upon exposure to additional, yet unknown risk factors ( 200 ). Furthermore, treatment with anti-PD-1 may first produce only a latent inflammatory involvement associated to dysregulated cardiac metabolism that may progress to overt myocarditis in a subset of patients ( 200 , 201 ).…”

Cardio-Oncology: A Myriad of Relationships Between Cardiovascular Disease and Cancer

“…Cardiotoxicity due to antineoplastic therapy is induced by multiple factors, mainly including oxidative stress ( 99 ) [OS; including mitochondrial functional impairment ( 100 ), myocardial apoptosis ( 101 , 102 )], microtubule dysfunction ( 103 , 104 ), and disruption of myocardial immune homeostasis ( 105 , 106 ).…”