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

Autor:	Michel L; Department of Cardiology and Vascular Medicine, West German Heart and Vascular Center, University Hospital Essen, Hufelandstraße 55, Essen 45147, Germany., Helfrich I; Department of Dermatology, University Hospital Essen, Hufelandstraße 55, Essen 45147, Germany.; German Cancer Consortium (DKTK), Partner Site Essen/Düsseldorf, Essen 45147, Germany.; Medical Faculty of the Ludwig Maximilian University of Munich, Department of Dermatology and Allergology, Frauenlobstrasse 9-11, Munich 80377, Germany., Hendgen-Cotta UB; Department of Cardiology and Vascular Medicine, West German Heart and Vascular Center, University Hospital Essen, Hufelandstraße 55, Essen 45147, Germany., Mincu RI; Department of Cardiology and Vascular Medicine, West German Heart and Vascular Center, University Hospital Essen, Hufelandstraße 55, Essen 45147, Germany., Korste S; Department of Cardiology and Vascular Medicine, West German Heart and Vascular Center, University Hospital Essen, Hufelandstraße 55, Essen 45147, Germany., Mrotzek SM; Department of Cardiology and Vascular Medicine, West German Heart and Vascular Center, University Hospital Essen, Hufelandstraße 55, Essen 45147, Germany., Spomer A; Department of Cardiology and Vascular Medicine, West German Heart and Vascular Center, University Hospital Essen, Hufelandstraße 55, Essen 45147, Germany., Odersky A; Department of Cardiology and Vascular Medicine, West German Heart and Vascular Center, University Hospital Essen, Hufelandstraße 55, Essen 45147, Germany., Rischpler C; Department of Nuclear Medicine, University Hospital Essen, Hufelandstraße 55, Essen 45147, Germany., Herrmann K; Department of Nuclear Medicine, University Hospital Essen, Hufelandstraße 55, Essen 45147, Germany., Umutlu L; Department of Diagnostic and Interventional Radiology and Neuroradiology, University Hospital Essen, Hufelandstraße 55, Essen 45147, Germany., Coman C; Institute for Analytical Chemistry, Waehringer Straße 38, Vienna A-1090, Austria.; Leibniz Institut für Analytische Wissenschaften-ISAS-e.V., Otto-Hahn-Straße 6b, Dortmund 44227, Germany., Ahrends R; Institute for Analytical Chemistry, Waehringer Straße 38, Vienna A-1090, Austria.; Leibniz Institut für Analytische Wissenschaften-ISAS-e.V., Otto-Hahn-Straße 6b, Dortmund 44227, Germany., Sickmann A; Leibniz Institut für Analytische Wissenschaften-ISAS-e.V., Otto-Hahn-Straße 6b, Dortmund 44227, Germany.; Medizinische Fakultät, Medizinisches Proteom-Center (MPC), Ruhr-Universität Bochum, Bochum 44801, Germany.; Department of Chemistry, College of Physical Sciences, University of Aberdeen, Aberdeen AB243FX, Scotland., Löffek S; Department of Dermatology, University Hospital Essen, Hufelandstraße 55, Essen 45147, Germany.; German Cancer Consortium (DKTK), Partner Site Essen/Düsseldorf, Essen 45147, Germany., Livingstone E; Department of Dermatology, University Hospital Essen, Hufelandstraße 55, Essen 45147, Germany.; German Cancer Consortium (DKTK), Partner Site Essen/Düsseldorf, Essen 45147, Germany., Ugurel S; Department of Dermatology, University Hospital Essen, Hufelandstraße 55, Essen 45147, Germany.; German Cancer Consortium (DKTK), Partner Site Essen/Düsseldorf, Essen 45147, Germany., Zimmer L; Department of Dermatology, University Hospital Essen, Hufelandstraße 55, Essen 45147, Germany.; German Cancer Consortium (DKTK), Partner Site Essen/Düsseldorf, Essen 45147, Germany., Gunzer M; Leibniz Institut für Analytische Wissenschaften-ISAS-e.V., Otto-Hahn-Straße 6b, Dortmund 44227, Germany.; Institute for Experimental Immunology and Imaging, University Hospital Essen, Hufelandstraße 55, Essen 45147, Germany., Schadendorf D; Department of Dermatology, University Hospital Essen, Hufelandstraße 55, Essen 45147, Germany.; German Cancer Consortium (DKTK), Partner Site Essen/Düsseldorf, Essen 45147, Germany., Totzeck M; Department of Cardiology and Vascular Medicine, West German Heart and Vascular Center, University Hospital Essen, Hufelandstraße 55, Essen 45147, Germany., Rassaf T; Department of Cardiology and Vascular Medicine, West German Heart and Vascular Center, University Hospital Essen, Hufelandstraße 55, Essen 45147, Germany.
Jazyk:	angličtina
Zdroj:	European heart journal [Eur Heart J] 2022 Jan 31; Vol. 43 (4), pp. 316-329.
DOI:	10.1093/eurheartj/ehab430
Abstrakt:	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. (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)
Databáze:	MEDLINE
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