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The Effect of PD-1 Inhibitor Combined with Irradiation on HMGB1-Associated Inflammatory Cytokines and Myocardial
Jie Bai1,2,3, Bibo Wu1,2,3, Shasha Zhao1,2,3
1Department of Oncology, The Affiliated Hospital of Guizhou Medical University, Guiyang, People's Republic of China.
Purpose:
To explore the effect of PD-1 inhibitors combined with irradiation on myocardial injury and the changes of HMGB1-associated inflammatory markers.
Methods:
Four groups of five mice were used, each groupformed by randomly dividing 20 mice (group A control; group B PD-1 inhibitors; group C Irradiation; group D PD-1 inhibitors+irradiation; n = 5 for each). The mice were treated with either PD-1 inhibitors or a 15 Gy dose of single heart irradiation, or both. Hematoxylin-eosin staining assessed the morphology and pathology of heart tissue; Masson staining assessed heart fibrosis; Tunel staining evaluated heart apoptosis; flow cytometry detected CD3+, CD4+, and CD8+ T lymphocytes in heart tissues; enzyme linked immunosorbent assay evaluated IL-1β, IL-6, and TNF-ɑ of heart tissue; Western blot and quantitative real-time PCR (qPCR) detected the expression of protein and mRNA of HMGB1, TLR-4, and NF-κB p65 respectively.
Results:
The degree of heart injury, collagen volume fraction (CVF) and apoptotic index (AI) in groups B, C, and D were higher than group A, but the differences between the CVF and AI of group A and group B were not statistical significance (P>0.05). Similarly, the absolute counts and relative percentage of CD3+ and CD8+ T lymphocytes and the concentrations of IL-1β, IL-6, and TNF-α in heart tissue with group D were significantly higher than the other groups (P<0.05). In addition, compared with group A, the expression of protein and mRNA of HMGB1 and NF-κB p65 in other groups were higher, and the differences between each group were statistically significant while TLR4 was not. In addition, interaction by PD-1 inhibitors and irradiation was found in inflammatory indicators, especially in the expression of the HMGB1 and CD8+ T lymphocytes.
Conclusion:
PD-1 inhibitors can increase the expression of HMGB1-associated inflammatory cytokines and aggravate radiation-induced myocardial injury.
Insights
Programmed cell death protein 1 (PD-1) inhibitors combined with irradiation worsen radiation-induced myocardial injury. This combination increases high-mobility group box 1 (HMGB1)-associated inflammatory cytokines and cardiac damage.
Area of Science:
- Cardiovascular research
- Immunotherapy
- Radiation oncology
Background:
- Myocardial injury is a potential side effect of cancer therapies.
- Programmed cell death protein 1 (PD-1) inhibitors are used in cancer treatment.
- Irradiation is a common cancer treatment modality.
Purpose of the Study:
- To investigate the combined effects of PD-1 inhibitors and irradiation on myocardial injury.
- To analyze changes in high-mobility group box 1 (HMGB1)-associated inflammatory markers.
Main Methods:
- A mouse model was used with four groups: control, PD-1 inhibitors alone, irradiation alone, and combined treatment.
- Histopathological analysis (Hematoxylin-eosin, Masson staining) and apoptosis assessment (Tunel staining) were performed.
- Flow cytometry, ELISA, Western blot, and qPCR were used to evaluate immune cell infiltration, inflammatory cytokines, and key protein/mRNA expression (HMGB1, TLR-4, NF-κB p65).
Main Results:
- Combined PD-1 inhibitors and irradiation significantly increased myocardial injury, fibrosis, and apoptosis compared to control and monotherapy groups.
- The combination therapy led to significantly higher levels of CD3+, CD8+ T lymphocytes, IL-1β, IL-6, and TNF-α in heart tissue.
- Expression of HMGB1 and NF-κB p65 was elevated in all treatment groups, with a significant interaction observed between PD-1 inhibitors and irradiation, particularly for HMGB1 and CD8+ T lymphocytes.
Conclusions:
- PD-1 inhibitors exacerbate radiation-induced myocardial injury.
- The combination therapy increases HMGB1-associated inflammatory cytokines.
- This study highlights the detrimental interaction between PD-1 inhibitors and irradiation on cardiac tissue.
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