PhD Scientific Days 2022

Translational Medicine I. (Poster discussion will take place on the terrace of the room during the Coffee Break)

Molecular determinants of immune checkpoint inhibitor-induced cardiac dysfunction: comparison of PD-1 inhibitor treated C57BL/6J and BALB/c mice

Előadó neve

Dr. Gergely, Tamás

Előadó munkahelye

Semmelweis University, Department of Pharmacology and Pharmacotherapy

Előadó telefonszáma

+36209504707

Előadó e-mail címe

gergely.tamas@med.semmelweis-univ.hu

Az előadás címe

Molecular determinants of immune checkpoint inhibitor-induced cardiac dysfunction: comparison of PD-1 inhibitor treated C57BL/6J and BALB/c mice

Szerző(k) neve és munkahelye

Tamás Gergely1,2,3, Dániel Kucsera1,2,3, Viktória E. Tóth1,2,3, Balázs Petrovich1, Bence Ágg1, Mihály Ruppert4, Zsófia Onódi1,2,3, Tamás Radovits4, Béla Merkely4, Péter Ferdinandy1,5, Zoltán V. Varga1,2,3
1Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary
2HCEMM-SU Cardiometabolic Immunology Research Group, Budapest, Hungary
3MTA-SE Momentum Cardio-Oncology and Cardioimmunology Research Group, Budapest, Hungary
4Heart and Vascular Center, Semmelweis University, Budapest, Hungary
5Pharmahungary Group, Szeged, Hungary

Bemutatás módja

Poszter

Szekció

Translational Medicine I. (Poster discussion will take place on the terrace of the room during the Coffee Break)

Language of the presentation

English

Preferred session

Theoretical and Translational Medicine

Összefoglaló szövege

Aims: Immune checkpoint inhibitors (ICI), such as anti-PD-1 monoclonal antibodies, have revolutionized the treatment of several malignancies by enhancing cytotoxic effects of T cells against tumours. However, enhanced T cell activity may cause myocarditis and cardiotoxicity. Nevertheless, our understanding of the mechanisms to ICI-induced cardiotoxicity are limited. We aimed to investigate the effect of PD-1 inhibition on cardiac function and to explore the molecular mechanisms of ICI-induced cardiotoxicity.
Method: 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 and validated by qRT-PCR. Inflammatory changes were assessed by qRT-PCR and immunohistochemistry in the heart, thymus and spleen of the animals, respectively. Cardiac 3-nitrotyrosin immunohistochemistry was performed to determine nitrosative stress.
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, with the increase of anti-inflammatory Il10 expression. Comparing myocardial transcriptomic changes in C57BL/6J and BALB/c mice, differentially regulated genes (Dmd, Ass1, Chrm2, Nfkbia, Stat3, Gsk3b, Cxcl9, Fxyd2, Ldb3) were revealed, related to cardiac structure, signalling and inflammation.
Conclusion: ICI-induced cardiac dysfunction presents with distinct myocardial transcriptomic profile and inflammatory signalling of the thymus, while the response to PD-1 inhibition differs across mouse strains.
Funding: The work was supported by the European Union’s Horizon 2020 Research and Innovation Programme under grant agreement no. 739593. TG was supported by “Semmelweis 250+ Kiválósági PhD Ösztöndíj” (EFOP-3.6.3-VEKOP-16-2017-00009) and by Gedeon Richter Talentum Foundation’s scholarship.

University and Doctoral School

Semmelweis University, Doctoral School of Pharmaceutical Sciences

Supervisor

Dr. Varga Zoltán

Publication of my abstract

I do not give consent to the publication of my abstract on the website of the congress.

Kind

Szabad

Status

elfogadva

Accepted presentation method

poszter

Előadás fájl jóváhagyás

nem rendelkezett róla

Előadó

6119

Start

11:20

End

11:25

Authors (legacy)

Tamás Gergely1,2,3, Dániel Kucsera1,2,3, Viktória E. Tóth1,2,3, Balázs Petrovich1, Bence Ágg1, Mihály Ruppert4, Zsófia Onódi1,2,3, Tamás Radovits4, Béla Merkely4, Péter Ferdinandy1,5, Zoltán V. Varga1,2,3
1Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary
2HCEMM-SU Cardiometabolic Immunology Research Group, Budapest, Hungary
3MTA-SE Momentum Cardio-Oncology and Cardioimmunology Research Group, Budapest, Hungary
4Heart and Vascular Center, Semmelweis University, Budapest, Hungary
5Pharmahungary Group, Szeged, Hungary