PhD Scientific Days 2025

Cardiovascular Medicine and Research I.

Thymic Activity Modulates Immune Checkpoint Inhibitor-Induced Cardiotoxicity: Implications for Therapeutic Strategies

Name of the presenter

Kocsis Márton

Institute/workplace of the presenter

Farmakológiai és Farmakoterápiás Intézet

Authors

Kocsis Márton¹, Kulin Anna¹, Szabó Lilla¹, Gergely Tamás¹, Sayour Viktor Nabil¹, Tóth Viktória¹, Hegedűs Zsombor¹, Tamás Kovács¹, Váradi Barnabás¹, Ferdinándy Péter¹, Varga Zoltán¹

1: Farmakológiai és Farmakoterápiás Intézet

Text of the abstract

Introduction: Immune checkpoint inhibitors (ICIs) have transformed cancer treatment, but their off target effects remain unclear. We previously showed that ICIs upregulate inflammatory genes in the thymus, and clinical use in thymoma patients has led to severe immune related adverse events, including fatal cardiotoxicity. We therefore hypothesized that thymic activity influences ICI induced autoimmunity.
Aims: To test this, we used a preclinical mouse model to examine how thymic function affects cardiac and systemic side effects during ICI therapy. Because thymic output declines with age, we treated both young and aged mice with a PD 1 inhibitor (or vehicle) three times weekly for two weeks. A third group of young mice received PD 1 blockade plus Azacitidine (AZA), which induces thymic involution.
Methods: Cardiac function was measured by echocardiography, inflammatory cytokine levels by qPCR, and tissue morphology via histology. We also profiled thymic gene expression (RNA seq, qPCR, RNAscope) and cellular composition (flow cytometry), and surveyed colon, lung, liver, kidney, and thyroid histopathology.
Results: In young mice, PD 1 inhibition triggered myocardial dysfunction, whereas aged animals and AZA treated young mice maintained normal ejection fraction. Thymic RNA seq revealed extensive transcriptional changes, and flow cytometry confirmed pathological alterations in thymic architecture. Histological analyses of peripheral organs were also evaluated.
Consclusions: Based on our results, thymic immune response plays a central role in ICI-induced cardiotoxicity in mice. In aged animals with degraded and less active thymuses undergoing ICI treatment and combined immunotherapy with pharmacologically induced involution of the thymus significantly reduced side effects, indicating that the immune response following ICI treatment varies depending on thymic activity. Thus, modulation of thymus activity may serve as a therapeutic target in reducing side effects and monitoring the morphology and activity may be an important factor in predicting the severity of side effects and identifying high-risk patients.
Fundings: Semmelweis 250+ Kiválósági PhD Ösztöndíj, VEKOP-2.3.2-16-2016-00002, RRF-2.3.1-21-2022-00003

kocsis.marton@semmelweis.hu
Semmelweis Egyetem, Farmakológiai és Farmakoterápiás Intézet
Dr. Varga Zoltán
I prefer to give an oral presentation.