PhD Scientific Days 2023

Budapest, 22-23 June 2023

Pathology - Posters C

Severity Of Immune Checkpoint Inhibition-Induced Cardiotoxicity Depends On Sex And Comorbidities: A Mouse Study

Nabil V. Sayour1,2, Dániel Kucsera1,2, Péter Ferdinandy1,3, Zoltán V. Varga1,2
1 – Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary
2 – HCEMM-SU Cardiometabolic Immunology Research Group, Budapest, Hungary
3 – Pharmahungary Group, Szeged, Hungary

Text of the abstract

INTRODUCTION: Immune checkpoint inhibitors (ICI) have revolutionized cancer therapy by enhancing the cytotoxic effects of T cells against tumors, however, cardiotoxic - and other immune-related adverse - effects of ICI therapies are increasingly recognized. Despite the accumulating data on underlying mechanisms, the influence of sex and cardiometabolic comorbidities on ICI-induced cardiotoxicity still remains to be investigated.
AIMS: To assess how ICI-induced cardiotoxicity is influenced by sex and cardiometabolic comorbidities in an aging mouse model.
METHODS: To this end, 17 months old male or female C57BL6/J mice were randomized into control diet (CON) or high fat diet plus L-NAME (HFD) groups (n=20-22). 15 weeks after initiation of diet, each group was randomized to receive PBS (VEH) or anti-PD-1 mAb (ICI) for 2 weeks, followed by termination. Echocardiography was performed 1 day before initiation of VEH or ICI treatment (baseline - BL), and at termination (TRM). Cardiac histology was performed for cell-surface-area (CSA) and microvascular density (MVD) measurements.
RESULTS: At BL, HFD caused no change in ejection fraction (EF), however, E/e´ was significantly increased in male HFD, but not in female HFD mice, compared to the corresponding CON groups. At TRM, ICI treatment led to a significantly decreased EF compared to BL in the CON diet groups of both sexes, but not in the HFD groups. CSA was significantly increased and MVD was significantly reduced in male HFD mice receiving ICI treatment, compared to corresponding CON and/or VEH groups. ICI treatment had no effect on CSA or MVD in female mice independently of HFD.
CONCLUSIONS: This is the first demonstration of measuring ICI-induced cardiotoxicity in aged mice of both sexes with cardiometabolic comorbidities. The causes of sex-, and diet-related differences in ICI-related cardiotoxicity will be investigated in the future, with a special emphasis on immune functions.
FUNDING: European Union's Horizon 2020 Research and Innovation Programme (739593), Momentum Research Grant from the Hungarian Academy of Sciences (LP-2021-14 to ZVV), NVKP_16-1-2016-0017, 2020-4.1.1.-TKP2020, EFOP-3.6.3-VEKOP-16-2017-00009, Gedeon Richter Talentum Foundation's scholarship