Characterization of immune checkpoint inhibitor-induced cardiotoxicity reveals interleukin-17A as a driver of cardiac dysfunction after anti-PD-1 treatment

Tamás G. Gergely; Dániel Kucsera; Viktória E. Tóth; Tamás Kovács; Nabil V. Sayour; Zsófia D. Drobni; Mihály Ruppert; Balázs Petrovich; Bence Ágg; Zsófia Onódi; Nóra Fekete; Éva Pállinger; Edit I. Buzás; Laura I. Yousif; Wouter C. Meijers; Tamás Radovits; Béla Merkely; Péter Ferdinandy; Zoltán V. Varga

doi:10.1111/bph.15984

Characterization of immune checkpoint inhibitor-induced cardiotoxicity reveals interleukin-17A as a driver of cardiac dysfunction after anti-PD-1 treatment

Tamás G. Gergely
, Dániel Kucsera
, Viktória E. Tóth
, Tamás Kovács
, Nabil V. Sayour
, Zsófia D. Drobni
, Mihály Ruppert
, Balázs Petrovich
, Bence Ágg
, Zsófia Onódi
, Nóra Fekete
, Éva Pállinger
, Edit I. Buzás
, Laura I. Yousif
, Wouter C. Meijers
, Tamás Radovits
, Béla Merkely
, Péter Ferdinandy
, Zoltán V. Varga^*

^*Corresponding author for this work

Semmelweis University
Pharmahungary Group
University Medical Centre Groningen
Erasmus University Rotterdam

Research output: Contribution to journal › Article › Academic › peer-review

68 Citations (Scopus)

71 Downloads (Pure)

Abstract

Background and Purpose: Immune checkpoint inhibitors (ICI), such as anti-PD-1 monoclonal antibodies, have revolutionized cancer therapy by enhancing the cytotoxic effects of T-cells against tumours. However, enhanced T-cell activity also may cause myocarditis and cardiotoxicity. Our understanding of the mechanisms of ICI-induced cardiotoxicity is limited. Here, we aimed to investigate the effect of PD-1 inhibition on cardiac function and explore the molecular mechanisms of ICI-induced cardiotoxicity. Experimental Approach: C57BL6/J and BALB/c mice were treated with isotype control or anti-PD-1 antibody. Echocardiography was used to assess cardiac function. Cardiac transcriptomic changes were investigated by bulk RNA sequencing. Inflammatory changes were assessed by qRT-PCR and immunohistochemistry in heart, thymus, and spleen of the animals. In follow-up experiments, anti-CD4 and anti-IL-17A antibodies were used along with PD-1 blockade in C57BL/6J mice. Key Results: Anti-PD-1 treatment led to cardiac dysfunction and left ventricular dilation in C57BL/6J mice, with increased nitrosative stress. Only mild inflammation was observed in the heart. However, PD-1 inhibition resulted in enhanced thymic inflammatory signalling, where Il17a increased most prominently. In BALB/c mice, cardiac dysfunction was not evident, and thymic inflammatory activation was more balanced. Inhibition of IL-17A prevented anti-PD-1-induced cardiac dysfunction in C57BL6/J mice. Comparing myocardial transcriptomic changes in C57BL/6J and BALB/c mice, differentially regulated genes (Dmd, Ass1, Chrm2, Nfkbia, Stat3, Gsk3b, Cxcl9, Fxyd2, and Ldb3) were revealed, related to cardiac structure, signalling, and inflammation. Conclusions: PD-1 blockade induces cardiac dysfunction in mice with increased IL-17 signalling in the thymus. Pharmacological inhibition of IL-17A treatment prevents ICI-induced cardiac dysfunction.

Original language	English
Pages (from-to)	740-761
Number of pages	22
Journal	British Journal of Pharmacology
Volume	180
Issue number	6
Early online date	10 Nov 2022
DOIs	https://doi.org/10.1111/bph.15984
Publication status	Published - Mar 2023
Externally published	Yes

Bibliographical note

Funding Information:
The work was supported by the European Union's Horizon 2020 Research and Innovation Programme under grant agreement no. 739593 and by a Momentum Research Grant from the Hungarian Academy of Sciences (LP‐2021‐14 to ZVV). Project no. RRF‐2.3.1‐21‐2022‐00003 has been implemented with the support provided by the European Union. NVKP_16‐1‐2016‐0017 (“National Heart Program”) has been implemented with the support provided from the National Research, Development and Innovation Fund of Hungary. The research was financed by the Thematic Excellence Programme (2020‐4.1.1.‐TKP2020) of the Ministry for Innovation and Technology in Hungary, within the framework of the Therapeutic Development and Bioimaging thematic programmes of the Semmelweis University, by grants VEKOP‐2.3.2‐16‐2016‐00002 and VEKOP‐2.3.3‐15‐2016‐00006, and by 2020‐1.1.6‐JÖVŐ‐2021‐00013 (“Befektetés a jövőbe” NKFIH). This project was supported by grants from the National Research, Development, and Innovation Office (NKFIH) of Hungary (K134939 to TR, FK134751 to ZVV). TGG, DK, NVS and ZO were supported by “Semmelweis 250+ Kiválósági PhD Ösztöndíj” (EFOP‐3.6.3‐VEKOP‐16‐2017‐00009). TGG and NVS was supported by Gedeon Richter Talentum Foundation's scholarship. ZVV was supported by the János Bolyai Research Scholarship of the Hungarian Academy of Sciences. BÁ, ZDD, DK and OZ were supported by the New National Excellence Program of the Ministry for Innovation and Technology from the source of the National Research, Development and Innovation Fund (ÚNKP‐20‐4‐I‐SE‐7, ÚNKP‐21‐4‐II‐SE‐18, ÚNKP‐19‐3‐SE‐I‐11, ÚNKP‐21‐3‐II and ÚNKP‐22‐4‐II‐SE‐3). Funding information

Publisher Copyright:
© 2022 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.

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Characterization of immune checkpoint inhibitor-induced cardiotoxicity reveals interleukin-17A as a driver of cardiac dysfunction after anti-PD-1 treatmentFinal published version, 8.67 MBLicence: CC BY

Cite this

Gergely, T. G., Kucsera, D., Tóth, V. E., Kovács, T., Sayour, N. V., Drobni, Z. D., Ruppert, M., Petrovich, B., Ágg, B., Onódi, Z., Fekete, N., Pállinger, É., Buzás, E. I., Yousif, L. I., Meijers, W. C., Radovits, T., Merkely, B., Ferdinandy, P., & Varga, Z. V. (2023). Characterization of immune checkpoint inhibitor-induced cardiotoxicity reveals interleukin-17A as a driver of cardiac dysfunction after anti-PD-1 treatment. British Journal of Pharmacology, 180(6), 740-761. https://doi.org/10.1111/bph.15984

@article{0f2fb14e6f664bba92deb16b85f157f8,

title = "Characterization of immune checkpoint inhibitor-induced cardiotoxicity reveals interleukin-17A as a driver of cardiac dysfunction after anti-PD-1 treatment",

abstract = "Background and Purpose: Immune checkpoint inhibitors (ICI), such as anti-PD-1 monoclonal antibodies, have revolutionized cancer therapy by enhancing the cytotoxic effects of T-cells against tumours. However, enhanced T-cell activity also may cause myocarditis and cardiotoxicity. Our understanding of the mechanisms of ICI-induced cardiotoxicity is limited. Here, we aimed to investigate the effect of PD-1 inhibition on cardiac function and explore the molecular mechanisms of ICI-induced cardiotoxicity. Experimental Approach: C57BL6/J and BALB/c mice were treated with isotype control or anti-PD-1 antibody. Echocardiography was used to assess cardiac function. Cardiac transcriptomic changes were investigated by bulk RNA sequencing. Inflammatory changes were assessed by qRT-PCR and immunohistochemistry in heart, thymus, and spleen of the animals. In follow-up experiments, anti-CD4 and anti-IL-17A antibodies were used along with PD-1 blockade in C57BL/6J mice. Key Results: Anti-PD-1 treatment led to cardiac dysfunction and left ventricular dilation in C57BL/6J mice, with increased nitrosative stress. Only mild inflammation was observed in the heart. However, PD-1 inhibition resulted in enhanced thymic inflammatory signalling, where Il17a increased most prominently. In BALB/c mice, cardiac dysfunction was not evident, and thymic inflammatory activation was more balanced. Inhibition of IL-17A prevented anti-PD-1-induced cardiac dysfunction in C57BL6/J mice. Comparing myocardial transcriptomic changes in C57BL/6J and BALB/c mice, differentially regulated genes (Dmd, Ass1, Chrm2, Nfkbia, Stat3, Gsk3b, Cxcl9, Fxyd2, and Ldb3) were revealed, related to cardiac structure, signalling, and inflammation. Conclusions: PD-1 blockade induces cardiac dysfunction in mice with increased IL-17 signalling in the thymus. Pharmacological inhibition of IL-17A treatment prevents ICI-induced cardiac dysfunction.",

author = "Gergely, \{Tam{\'a}s G.\} and D{\'a}niel Kucsera and T{\'o}th, \{Vikt{\'o}ria E.\} and Tam{\'a}s Kov{\'a}cs and Sayour, \{Nabil V.\} and Drobni, \{Zs{\'o}fia D.\} and Mih{\'a}ly Ruppert and Bal{\'a}zs Petrovich and Bence {\'A}gg and Zs{\'o}fia On{\'o}di and N{\'o}ra Fekete and {\'E}va P{\'a}llinger and Buz{\'a}s, \{Edit I.\} and Yousif, \{Laura I.\} and Meijers, \{Wouter C.\} and Tam{\'a}s Radovits and B{\'e}la Merkely and P{\'e}ter Ferdinandy and Varga, \{Zolt{\'a}n V.\}",

note = "Funding Information: The work was supported by the European Union's Horizon 2020 Research and Innovation Programme under grant agreement no. 739593 and by a Momentum Research Grant from the Hungarian Academy of Sciences (LP‐2021‐14 to ZVV). Project no. RRF‐2.3.1‐21‐2022‐00003 has been implemented with the support provided by the European Union. NVKP\_16‐1‐2016‐0017 (“National Heart Program”) has been implemented with the support provided from the National Research, Development and Innovation Fund of Hungary. The research was financed by the Thematic Excellence Programme (2020‐4.1.1.‐TKP2020) of the Ministry for Innovation and Technology in Hungary, within the framework of the Therapeutic Development and Bioimaging thematic programmes of the Semmelweis University, by grants VEKOP‐2.3.2‐16‐2016‐00002 and VEKOP‐2.3.3‐15‐2016‐00006, and by 2020‐1.1.6‐J{\"O}V{\H O}‐2021‐00013 (“Befektet{\'e}s a j{\"o}v{\H o}be” NKFIH). This project was supported by grants from the National Research, Development, and Innovation Office (NKFIH) of Hungary (K134939 to TR, FK134751 to ZVV). TGG, DK, NVS and ZO were supported by “Semmelweis 250+ Kiv{\'a}l{\'o}s{\'a}gi PhD {\"O}szt{\"o}nd{\'i}j” (EFOP‐3.6.3‐VEKOP‐16‐2017‐00009). TGG and NVS was supported by Gedeon Richter Talentum Foundation's scholarship. ZVV was supported by the J{\'a}nos Bolyai Research Scholarship of the Hungarian Academy of Sciences. B{\'A}, ZDD, DK and OZ were supported by the New National Excellence Program of the Ministry for Innovation and Technology from the source of the National Research, Development and Innovation Fund ({\'U}NKP‐20‐4‐I‐SE‐7, {\'U}NKP‐21‐4‐II‐SE‐18, {\'U}NKP‐19‐3‐SE‐I‐11, {\'U}NKP‐21‐3‐II and {\'U}NKP‐22‐4‐II‐SE‐3). Funding information Publisher Copyright: {\textcopyright} 2022 The Authors. British Journal of Pharmacology published by John Wiley \& Sons Ltd on behalf of British Pharmacological Society.",

year = "2023",

month = mar,

doi = "10.1111/bph.15984",

language = "English",

volume = "180",

pages = "740--761",

journal = "British Journal of Pharmacology",

issn = "0007-1188",

publisher = "John Wiley \& Sons Inc.",

number = "6",

}

Gergely, TG, Kucsera, D, Tóth, VE, Kovács, T, Sayour, NV, Drobni, ZD, Ruppert, M, Petrovich, B, Ágg, B, Onódi, Z, Fekete, N, Pállinger, É, Buzás, EI, Yousif, LI, Meijers, WC, Radovits, T, Merkely, B, Ferdinandy, P & Varga, ZV 2023, 'Characterization of immune checkpoint inhibitor-induced cardiotoxicity reveals interleukin-17A as a driver of cardiac dysfunction after anti-PD-1 treatment', British Journal of Pharmacology, vol. 180, no. 6, pp. 740-761. https://doi.org/10.1111/bph.15984

Characterization of immune checkpoint inhibitor-induced cardiotoxicity reveals interleukin-17A as a driver of cardiac dysfunction after anti-PD-1 treatment. / Gergely, Tamás G.; Kucsera, Dániel; Tóth, Viktória E. et al.
In: British Journal of Pharmacology, Vol. 180, No. 6, 03.2023, p. 740-761.

Research output: Contribution to journal › Article › Academic › peer-review

TY - JOUR

T1 - Characterization of immune checkpoint inhibitor-induced cardiotoxicity reveals interleukin-17A as a driver of cardiac dysfunction after anti-PD-1 treatment

AU - Gergely, Tamás G.

AU - Kucsera, Dániel

AU - Tóth, Viktória E.

AU - Kovács, Tamás

AU - Sayour, Nabil V.

AU - Drobni, Zsófia D.

AU - Ruppert, Mihály

AU - Petrovich, Balázs

AU - Ágg, Bence

AU - Onódi, Zsófia

AU - Fekete, Nóra

AU - Pállinger, Éva

AU - Buzás, Edit I.

AU - Yousif, Laura I.

AU - Meijers, Wouter C.

AU - Radovits, Tamás

AU - Merkely, Béla

AU - Ferdinandy, Péter

AU - Varga, Zoltán V.

N1 - Funding Information: The work was supported by the European Union's Horizon 2020 Research and Innovation Programme under grant agreement no. 739593 and by a Momentum Research Grant from the Hungarian Academy of Sciences (LP‐2021‐14 to ZVV). Project no. RRF‐2.3.1‐21‐2022‐00003 has been implemented with the support provided by the European Union. NVKP_16‐1‐2016‐0017 (“National Heart Program”) has been implemented with the support provided from the National Research, Development and Innovation Fund of Hungary. The research was financed by the Thematic Excellence Programme (2020‐4.1.1.‐TKP2020) of the Ministry for Innovation and Technology in Hungary, within the framework of the Therapeutic Development and Bioimaging thematic programmes of the Semmelweis University, by grants VEKOP‐2.3.2‐16‐2016‐00002 and VEKOP‐2.3.3‐15‐2016‐00006, and by 2020‐1.1.6‐JÖVŐ‐2021‐00013 (“Befektetés a jövőbe” NKFIH). This project was supported by grants from the National Research, Development, and Innovation Office (NKFIH) of Hungary (K134939 to TR, FK134751 to ZVV). TGG, DK, NVS and ZO were supported by “Semmelweis 250+ Kiválósági PhD Ösztöndíj” (EFOP‐3.6.3‐VEKOP‐16‐2017‐00009). TGG and NVS was supported by Gedeon Richter Talentum Foundation's scholarship. ZVV was supported by the János Bolyai Research Scholarship of the Hungarian Academy of Sciences. BÁ, ZDD, DK and OZ were supported by the New National Excellence Program of the Ministry for Innovation and Technology from the source of the National Research, Development and Innovation Fund (ÚNKP‐20‐4‐I‐SE‐7, ÚNKP‐21‐4‐II‐SE‐18, ÚNKP‐19‐3‐SE‐I‐11, ÚNKP‐21‐3‐II and ÚNKP‐22‐4‐II‐SE‐3). Funding information Publisher Copyright: © 2022 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.

PY - 2023/3

Y1 - 2023/3

N2 - Background and Purpose: Immune checkpoint inhibitors (ICI), such as anti-PD-1 monoclonal antibodies, have revolutionized cancer therapy by enhancing the cytotoxic effects of T-cells against tumours. However, enhanced T-cell activity also may cause myocarditis and cardiotoxicity. Our understanding of the mechanisms of ICI-induced cardiotoxicity is limited. Here, we aimed to investigate the effect of PD-1 inhibition on cardiac function and explore the molecular mechanisms of ICI-induced cardiotoxicity. Experimental Approach: C57BL6/J and BALB/c mice were treated with isotype control or anti-PD-1 antibody. Echocardiography was used to assess cardiac function. Cardiac transcriptomic changes were investigated by bulk RNA sequencing. Inflammatory changes were assessed by qRT-PCR and immunohistochemistry in heart, thymus, and spleen of the animals. In follow-up experiments, anti-CD4 and anti-IL-17A antibodies were used along with PD-1 blockade in C57BL/6J mice. Key Results: Anti-PD-1 treatment led to cardiac dysfunction and left ventricular dilation in C57BL/6J mice, with increased nitrosative stress. Only mild inflammation was observed in the heart. However, PD-1 inhibition resulted in enhanced thymic inflammatory signalling, where Il17a increased most prominently. In BALB/c mice, cardiac dysfunction was not evident, and thymic inflammatory activation was more balanced. Inhibition of IL-17A prevented anti-PD-1-induced cardiac dysfunction in C57BL6/J mice. Comparing myocardial transcriptomic changes in C57BL/6J and BALB/c mice, differentially regulated genes (Dmd, Ass1, Chrm2, Nfkbia, Stat3, Gsk3b, Cxcl9, Fxyd2, and Ldb3) were revealed, related to cardiac structure, signalling, and inflammation. Conclusions: PD-1 blockade induces cardiac dysfunction in mice with increased IL-17 signalling in the thymus. Pharmacological inhibition of IL-17A treatment prevents ICI-induced cardiac dysfunction.

AB - Background and Purpose: Immune checkpoint inhibitors (ICI), such as anti-PD-1 monoclonal antibodies, have revolutionized cancer therapy by enhancing the cytotoxic effects of T-cells against tumours. However, enhanced T-cell activity also may cause myocarditis and cardiotoxicity. Our understanding of the mechanisms of ICI-induced cardiotoxicity is limited. Here, we aimed to investigate the effect of PD-1 inhibition on cardiac function and explore the molecular mechanisms of ICI-induced cardiotoxicity. Experimental Approach: C57BL6/J and BALB/c mice were treated with isotype control or anti-PD-1 antibody. Echocardiography was used to assess cardiac function. Cardiac transcriptomic changes were investigated by bulk RNA sequencing. Inflammatory changes were assessed by qRT-PCR and immunohistochemistry in heart, thymus, and spleen of the animals. In follow-up experiments, anti-CD4 and anti-IL-17A antibodies were used along with PD-1 blockade in C57BL/6J mice. Key Results: Anti-PD-1 treatment led to cardiac dysfunction and left ventricular dilation in C57BL/6J mice, with increased nitrosative stress. Only mild inflammation was observed in the heart. However, PD-1 inhibition resulted in enhanced thymic inflammatory signalling, where Il17a increased most prominently. In BALB/c mice, cardiac dysfunction was not evident, and thymic inflammatory activation was more balanced. Inhibition of IL-17A prevented anti-PD-1-induced cardiac dysfunction in C57BL6/J mice. Comparing myocardial transcriptomic changes in C57BL/6J and BALB/c mice, differentially regulated genes (Dmd, Ass1, Chrm2, Nfkbia, Stat3, Gsk3b, Cxcl9, Fxyd2, and Ldb3) were revealed, related to cardiac structure, signalling, and inflammation. Conclusions: PD-1 blockade induces cardiac dysfunction in mice with increased IL-17 signalling in the thymus. Pharmacological inhibition of IL-17A treatment prevents ICI-induced cardiac dysfunction.

UR - https://www.scopus.com/pages/publications/85144047789

U2 - 10.1111/bph.15984

DO - 10.1111/bph.15984

M3 - Article

C2 - 36356191

AN - SCOPUS:85144047789

SN - 0007-1188

VL - 180

SP - 740

EP - 761

JO - British Journal of Pharmacology

JF - British Journal of Pharmacology

IS - 6

ER -

Characterization of immune checkpoint inhibitor-induced cardiotoxicity reveals interleukin-17A as a driver of cardiac dysfunction after anti-PD-1 treatment

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