ATP protects anti-PD-1/radiation-induced cardiac dysfunction by inhibiting anti-PD-1 exacerbated cardiomyocyte apoptosis, and improving autophagic flux

Jing Wang; Jing Zhao; Zhijun Meng; Rui Guo; Ruihong Yang; Caihong Liu; Jia Gao; Yaoli Xie; Xiangying Jiao; Heping Fang; Jianli Zhao; Yajing Wang; Jimin Cao

doi:10.1016/j.heliyon.2023.e20660

ATP protects anti-PD-1/radiation-induced cardiac dysfunction by inhibiting anti-PD-1 exacerbated cardiomyocyte apoptosis, and improving autophagic flux

Heliyon. 2023 Oct 5;9(10):e20660. doi: 10.1016/j.heliyon.2023.e20660. eCollection 2023 Oct.

Authors

Jing Wang^{1

2}, Jing Zhao¹, Zhijun Meng¹, Rui Guo¹, Ruihong Yang², Caihong Liu¹, Jia Gao¹, Yaoli Xie¹, Xiangying Jiao¹, Heping Fang¹, Jianli Zhao³, Yajing Wang³, Jimin Cao¹

Affiliations

¹ Department of Physiology, Shanxi Medical University, Taiyuan, Shanxi 030001, China.
² Department of Thoracic Radiotherapy, Shanxi Provincial Cancer Hospital, Taiyuan, Shanxi 030013, China.
³ Department of Biomedical Engineering, University of Alabama at Birmingham, AL 35294, USA.

Abstract

The synergy between radiotherapy and immunotherapy in treating thoracic cancers presents a potent therapeutic advantage, yet it also carries potential risks. The extent and nature of cumulative cardiac toxicity remain uncertain, prompting the need to discern its mechanisms and devise effective mitigation strategies. Radiation alone or in combination with an anti- Programmed cell death protein1 (PD-1) antibody significantly reduced cardiac function in C57BL/6J mice, and this pathologic effect was aggravated by anti-PD-1 (anti-PD-1 + radiation). To examine the cellular mechanism that causes the detrimental effect of anti-PD-1 upon cardiac function after radiation, AC16 human cardiomyocytes were used to study cardiac apoptosis and cardiac autophagy. Radiation-induced cardiomyocyte apoptosis was significantly promoted by anti-PD-1 treatment, while anti-PD-1 combined radiation administration blocked the cardiac autophagic flux. Adenosine 5'-triphosphate (ATP) (a molecule that promotes lysosomal acidification) not only improved autophagic flux in AC16 human cardiomyocytes, but also attenuated apoptosis induced by radiation and anti-PD-1 treatment. Finally, ATP administration in vivo significantly reduced radiation-induced and anti-PD-1-exacerbated cardiac dysfunction. We demonstrated for the first time that anti-PD-1 can aggravate radiation-induced cardiac dysfunction via promoting cardiomyocyte apoptosis without affecting radiation-arrested autophagic flux. ATP enhanced cardiomyocyte autophagic flux and inhibited apoptosis, improving cardiac function in anti-PD-1/radiation combination-treated animals.

Keywords: Anti-PD-1 antibody; Apoptosis; Autophagy; Cardiotoxicity; Radiation.