Y. Mo1,2, M. Wu2, B. Tian2, D. Chen2, and J. Yu1,2; 1The First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, China, 2Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
Purpose/Objective(s): Cardiac toxicity is a severe adverse effect of cancer treatments (radiotherapy (RT), chemotherapy, immunotherapy (ICB), and targeted therapy) leading to cardiomyopathy, cardiac failure, arrhythmias, and coronary disorders. Herein, we explored the impact of radiotherapy alone or in combination with other therapies on various cardiac toxicities, with specific focus on the role of PDL-1 in radiation-induced heart disease (RIHD). Materials/
Methods: We utilize the FDA Adverse Event Reporting System to evaluate cardiac toxicity (arrhythmias, cardiac failure, pericardial, myocardial, coronary artery) from monotherapy and combination therapies through disproportionality analysis. Mouse models were established based on evaluation of histopathological characteristics, cardiac magnetic resonance imaging, electrocardiogram and biomarkers. Single cell RNA-sequencing (scRNA-seq) of RIHD models were performed to characterize the diversity within specific cell types and obtain significant signaling pathway, followed by flow cytometry, western blot and multi-immunofluorescence to illustrate PDL-1 expression of cell subsets in RIHD, finally validated from autopsy heart samples of patients with cardiomyopathy. Results: RT increased the risk of cardiac disorders (RT vs ICB: ROR=3.203, P<0.01; RT vs target therapy =4.134, P<0.01; RT vs chemotherapy: ROR=4.335, P<0.01). Males had higher risk than females (Males vs Females: ROR=1.081, P=0.018) in cardiac disorders. A combination of ICB and RT has the least impact on the cardiac disorder (ICB-RT vs RT: ROR=0.031, P<0.01; ICB-RT vs ICB: ROR=0.356, P<0.01; ICB-RT vs ICB-CHEMO: ROR=0.401, P<0.01; ICB-RT vs ICB-TARGET: ROR=0.347, P<0.01; CHEMO-RT vs ICB-RT: ROR=3.626, P<0.01; TARGET-RT vs ICB-RT: ROR=3.380, P<0.01; TARGET-CHEMO vs ICB-RT: ROR=2.308, P<0.01). And anti-PDL-1 had lower effect on cardiac failure (anti-PDL-1 vs anti-PD-1: HR=0.168, P<0.01;anti- PDL-1 vs anti-CTLA-4: HR=0.048, P<0.01) and coronary artery disorders (anti-PDL-1 vs anti-PD-1: HR=0.049, P</i><0.01). Analysis of scRNA-seq revealed that PDL-1 signaling pathway was up-regulated during the compensatory stage of RIHD. Cell-specific (Vimentin+cells) PDL-1 in progression of RIHD were found to be associated with collagen deposition in mouse model and autopsy heart samples of patients with cardiomyopathy. Conclusion: RT posed the highest risk of cardiac toxicity, particularly in cardiac arrhythmias. RT combined with chemotherapy increased the risk of cardiac coronary disorders and cardiac arrhythmia compared to other combination therapies. Additionally, RT combined with targeted therapy raised the risk of cardiac failure. Notably, compared to RT, PDL-1 combined with RT decreased risk of cardiac failure toxicity and coronary artery toxicity in NSCLC patients. The PDL-1 expression of fibroblasts in irradiated heart may explain the mechanism. The finding provided a new insight to investigate cardiac toxicity in NSCLC patients received RT.
