Immune checkpoint inhibition with PD-1 inhibitor induces cardiac dysfunction without overt myocarditis in C57BL/6J mice Article Swipe
T Gergely
,
Dániel Kucsera
,
VE Toth
,
Balázs Petrovich
,
Bence Ágg
,
ZS Onodi
,
Mihály Ruppert
,
Tamás Radovits
,
B Merkely
,
Péter Ferdinandy
,
ZV Varga
·
YOU?
·
· 2022
· Open Access
·
· DOI: https://doi.org/10.1093/cvr/cvac066.081
YOU?
·
· 2022
· Open Access
·
· DOI: https://doi.org/10.1093/cvr/cvac066.081
Funding Acknowledgements Type of funding sources: Public grant(s) – EU funding. Main funding source(s): European Union’s Horizon 2020 Research and Innovation Programme under grant agreement no. 739593 “Semmelweis 250+ Kiválósági PhD Ösztöndíj” (EFOP-3.6.3-VEKOP-16-2017-00009) Gedeon Richter Talentum Foundation’s scholarship Background Immune checkpoint inhibitors have revolutionized the treatment of several form of malignancies (including metastatic melanoma) by enhancing the cytotoxic effects of T cells against cancer cells. Cancer cells evade immune surveillence by increasing the expression of T cell inhibitory molecules, also known as immune checkpoints, such as programmed cell death-1 (PD-1). Pharmacological inhibition of these molecules by immune checkpoint inhibitors (ICI) will enhance the antitumor activity of T cells. However, enhanced T cell activity may cause immune related adverse effects, including cardiotoxicity. Aims We aimed to investigate the effect of PD-1 inhibition on cardiac function and the underlying mechanisms in mice. Methods 8-10 weeks old C57BL6/J mice were treated with isotype control or anti-PD-1 antibody for 2 or 4 weeks. Cardiac function and morphology was assessed by echocardiography and histology, while the transcriptomic changes were analyzed via RNA sequencing. Nitrosative stress in the heart was assessed by immunohistochemistry and qRT-PCR. Inflammatory gene expression alterations were determined by qRT-PCR in the heart and thymus. Results Small animal echocardiography revealed cardiac dysfunction even after 2 weeks of anti-PD-1 treatment, with distinct transcriptomic changes. Nitrosative stress was found to be elevated in the myocardium due to anti-PD-1 treatment, however, histological and qRT-PCR analysis did not reveal T cell infiltration into the myocardium and only mild inflammation was seen in the heart. In contrast, inflammatory gene expression was significantly enhanced in the thymus of anti-PD-1-treated animals, where interleukin-17 showed the most prominent increase. Conclusions These findings characterize cardiac dysfunction as a form of ICI-induced cardiotoxicity, which may be mediated by increased thymic inflammatory activation and cytokine production.
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- Type
- article
- Language
- en
- Landing Page
- https://doi.org/10.1093/cvr/cvac066.081
- https://academic.oup.com/cardiovascres/article-pdf/118/Supplement_1/cvac066.081/44155250/cvac066.081.pdf
- OA Status
- bronze
- Related Works
- 10
- OpenAlex ID
- https://openalex.org/W4281699018
All OpenAlex metadata
Raw OpenAlex JSON
- OpenAlex ID
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https://openalex.org/W4281699018Canonical identifier for this work in OpenAlex
- DOI
-
https://doi.org/10.1093/cvr/cvac066.081Digital Object Identifier
- Title
-
Immune checkpoint inhibition with PD-1 inhibitor induces cardiac dysfunction without overt myocarditis in C57BL/6J miceWork title
- Type
-
articleOpenAlex work type
- Language
-
enPrimary language
- Publication year
-
2022Year of publication
- Publication date
-
2022-06-01Full publication date if available
- Authors
-
T Gergely, Dániel Kucsera, VE Toth, Balázs Petrovich, Bence Ágg, ZS Onodi, Mihály Ruppert, Tamás Radovits, B Merkely, Péter Ferdinandy, ZV VargaList of authors in order
- Landing page
-
https://doi.org/10.1093/cvr/cvac066.081Publisher landing page
- PDF URL
-
https://academic.oup.com/cardiovascres/article-pdf/118/Supplement_1/cvac066.081/44155250/cvac066.081.pdfDirect link to full text PDF
- Open access
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YesWhether a free full text is available
- OA status
-
bronzeOpen access status per OpenAlex
- OA URL
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https://academic.oup.com/cardiovascres/article-pdf/118/Supplement_1/cvac066.081/44155250/cvac066.081.pdfDirect OA link when available
- Concepts
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Immune system, Immune checkpoint, Cardiotoxicity, Cancer research, Myocarditis, Biology, Cardiac function curve, Melanoma, Cytotoxic T cell, Internal medicine, Immunology, Medicine, Immunotherapy, Heart failure, Chemotherapy, In vitro, BiochemistryTop concepts (fields/topics) attached by OpenAlex
- Cited by
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0Total citation count in OpenAlex
- Related works (count)
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10Other works algorithmically related by OpenAlex
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