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PD-1 Inhibitor Aggravate Irradiation-Induced Myocardial Fibrosis by Regulating TGF-β1/Smads Signaling Pathway via GSDMD-Mediated Pyroptosis

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Abstract

Cancer therapy has entered a new era with the use of programmed cell death protein 1 (PD-1) immune checkpoint inhibitors. When combined with thoracic radiotherapy, it demonstrates synergistic anti-tumor effects and potentially worsens radiation-induced myocardial fibrosis (RIMF). RIMF is the final stage of radiation-induced heart disease (RIHD) and a potentially fatal clinical complication of chest radiotherapy. It is characterized by decreased ventricular elasticity and distensibility, which can result in decreased ejection fraction, heart failure, and even sudden cardiac death. Pyroptosis, a type of programmed cell death, is mediated by members of the gasdermin (GSDM) family and has been associated with numerous cardiac disorders. The effect of pyroptosis on myocardial fibrosis caused by a combination of radiotherapy and PD-1 inhibitors remains uncertain. In this study, a 6MV X-ray of 20 Gy for local heart irradiation was used in the RIHD mouse model. We noticed that PD-1 inhibitors aggravated radiation-induced cardiac dysfunction and RIMF, concurrently enhancing the presence of CD8+ T lymphocytes in the cardiac tissue. Additionally, our findings indicated that the combination of PD-1 inhibitor and thoracic radiation can stimulate caspase-1 to cleave GSDMD, thereby regulating pyroptosis and liberating interleukin-8 (IL-18). In the myocardium of mice, the manifestation of pyroptosis mediated by GSDMD is accompanied by the buildup of proteins associated with fibrosis, such as collagen I, transforming growth factor β1 (TGF-β1), interleukin-6 (IL-6), vascular endothelial growth factor (VEGF), and tumor necrosis factor α (TNF-α). Moreover, it was discovered that TFG-β1 induced the phosphorylation of Smad2/Smad3 when the cardiac underwent PD-1 inhibitor in conjunction with thoracic irradiation (IR). The findings of this research indicate that PD-1 inhibitor worsen RIMF in mice by triggering GSDMD-induced pyroptosis and influencing the TGF-β1/Smads pathway. While using the caspase-1 inhibitor Z-YVAD-FMK, RIMF can be alleviated. Blocking GSDMD may be a viable strategy for managing myocardial fibrosis caused by the combination of PD-1 inhibitors and radiotherapy.

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No datasets were generated or analysed during the current study.

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Funding

This work was supported by the National Natural Science Foundation of China [grant number 81960548] and the Guizhou Provincial Natural Science Foundation, China [ZK (2022) key040].

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Author notes

  1. Bibo Wu, Shasha Zhao, **g Zhang and Yao Liu contributed equally to this work.

Authors and Affiliations

  1. Department of Oncology, Affiliated Hospital of Guizhou Medical University, Guiyang, China

    Bibo Wu, Shasha Zhao, **g Zhang, Yao Liu, Jie Bai, Gang Wang, Yu Wang, Han Jiang, Yinxiang Hu, Weiwei OuYang, Bing Lu & Shengfa Su

  2. Department of Oncology, Affiliated Cancer Hospital of Guizhou Medical University, Guiyang, China

    Bibo Wu, Shasha Zhao, **g Zhang, Yao Liu, Jie Bai, Gang Wang, Yu Wang, Han Jiang, Yinxiang Hu, Weiwei OuYang, Bing Lu & Shengfa Su

  3. Teaching and Research Department of Oncology, Clinical Medical College of Guizhou Medical University, Guiyang, China

    Bibo Wu, Shasha Zhao, **g Zhang, Yao Liu, Jie Bai, Gang Wang, Yu Wang, Han Jiang, Yinxiang Hu, Weiwei OuYang, Bing Lu & Shengfa Su

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Contributions

Bibo Wu: Designed and performed the experiments, Data Analysis, Writing manuscript; Shasha Zhao: Conducted partial animal experiments; Writing Original Draft; **g Zhang: Analyzed the data and interpreted the experimental results; Yao Liu and Jie Bai: Data Analysis and modify the article; Gang Wang: Data Curation; Yu Wang and Han Jiang: Helped with Modeling in Animals; Yinxiang Hu: Guide radiation physics techniques; Weiwei Ouyang and Bing Lu: Resources, Supervision; Shengfa Su (Corresponding Author): Conceived the project, Funding Acquisition, Planned and directed this research Project.

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Correspondence to Shengfa Su.

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Limitations

There are some limitations to this study. First of all, in most animal models established by researchers to explore the mechanism of RIHD, the irradiation method is to receive the same dose of whole-heart irradiation, which does not involve in vivo tumors. However, in clinical practice, the radiation dose received by different areas in the heart of patients with thoracic tumors varies greatly. A single dose of 20 Gy to the heart is not directly related to exposure to radiation therapy. Secondly, only male mice were studied, and the effects on female mice may be different. Thirdly, each of the analyses contained a very small number of mice.

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Wu, B., Zhao, S., Zhang, J. et al. PD-1 Inhibitor Aggravate Irradiation-Induced Myocardial Fibrosis by Regulating TGF-β1/Smads Signaling Pathway via GSDMD-Mediated Pyroptosis. Inflammation (2024). https://doi.org/10.1007/s10753-024-02056-9

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