Abstract
Purpose
Programmed cell death protein 1 (PD-1) inhibitors may further increase the risk of cardiotoxicity of radiotherapy while improving the outcomes of locally advanced lung cancer. However, few studies have focused on cardiac injury caused by radiotherapy plus anti-PD-1 therapy, and the underlying mechanism is still under exploration. This study aimed to explore this mechanism.
Methods
Six- to eight-week-old C57BL/6 mice were treated with either an anti-PD-1 antibody or phosphate-buffered saline (PBS) with or without 15 Gray (Gy) cardiac irradiation (IR). Five mice were sacrificed at 1 month, and the remaining mice were sacrificed at 3 months. Histological analysis was performed to determine the structural and morphological alterations and cardiac fibrosis. The infiltration of cardiac T cells was analysed via flow cytometry, and western blotting and qPCR were used to detect the protein and mRNA expression levels of HMGB1-related pathway.
Results
Group D (IR + anti-PD-1) demonstrated more severe injury, fibrosis, and apoptosis compared to groups A (control), B (anti-PD-1), and C (IR). Furthermore, the injury observed in Group D was significantly more severe, with higher values of apoptotic index (AI) and fibrotic area at 3 months compared to 1 month (P < 0.05). At 1 month, there were no significant differences in cardiac damage or AI or CVF values between groups A and B, but these differences emerged at 3 months (P < 0.05). Group D exhibited greater infiltration of T lymphocytes and increased expression of high mobility group box-1 protein (HMGB1), Toll-like receptor 4 (TLR4), and nuclear factor kappa-B (NF-κB P65) at both 1 and 3 months compared to the other three groups.
Conclusion
In combination with radiation, PD-1 inhibitors exacerbated myocardial injury by modulating the HMGB1/NF-κB signalling pathway.