Cardiotoxicity of Anti-PD-L1 Antibody and the Effect of Levothyroxine
in Attenuating the Related Mortality in Mice.
10.3779/j.issn.1009-3419.2021.102.23
- Author:
Zhenyin CHEN
1
;
Min WANG
2
;
Sanhui GAO
2
;
Hua GUO
3
;
Guizhen WANG
3
;
Guangbiao ZHOU
3
Author Information
1. Guizhou University School of Medicine, Guiyang 550025, China.
2. State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Acadamy of Science, Beijing 100101, China.
3. State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100021, China.
- Publication Type:Journal Article
- Keywords:
Cardiotoxicity;
Programmed cell death ligand 1;
Thyroid
- From:
Chinese Journal of Lung Cancer
2021;24(6):394-403
- CountryChina
- Language:Chinese
-
Abstract:
BACKGROUND:Immune checkpoint inhibitors (ICIs) such as antibodies against programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1), have shown remarkable efficacies in many subtypes of cancers. However, ICIs may also cause severe immune-related adverse events in the recipient patients. Recently, ICI-associated myocarditis have been reported in hundreds of patients worldwide, with a mortality rate of approximately 50% in these cases. This study aims to recapitulate the cardiotoxicity and explore the detoxicifying approaches to attenuate mortality caused by PD-1/PD-L1 inhibitors in healthy mice.
METHODS:Six to eight-week-old C57BL/6 mice were inoculated with anti-PD-1 antibody (12.5 μg/g every 5 days for 6 injections), anti-PD-L1 antibody (10 μg/g once a week for 6 weeks), anti-PD-L1 antibody (with the same dosage described above) in combination with levothyroxine (0.25 μg/g, intraperitoneally injected half an hour before anti-PD-L1 antibody injection), or isotype control immunoglobulin IgG (10 μg/g once a week for 6 weeks). The ejection function of the hearts was detected by echocardiography, body temperature and blood pressure were detected by Mouse MonitorTM and non-invassive blood pressure minotor, and serum free thyroxine concentration was detected by The enzyme linked immunosorbent assay (ELISA).
RESULTS:PD-L1 was expressed at different levels by the cardiomyocytes of the mice. The isotype control immunoglobulin and anti-PD-1 antibody did not cause death of the mice. The 12 mice receiving 3-6 injections of anti-PD-L1 antibody showed a significant increase in the heart-to-tibial ratio and cardiomyoctye degeneration, hyalinization and extravascular inflammatory cell infiltration. In addition, the serum thyroxine was mardedly decreased to 1/3 of that in the control group mice, and the blood pressure and body temperature were abnormally decreased in mice upon treatment with PD-L1 blockade. Eight of the 12 (66.7%) mice died from multiple intravenous injection of anti-PD-L1 antibody.Intraperitoneal injection of levothyroxine 30 min before the injection of anti-PD-L1 antibody significantly attenuated the mortality rate of the anti-PD-L1 antibody-treated mice.
CONCLUSIONS:The anti-PD-L1 antibody is cardiotoxic and lethal, and levothyroxine is able to rescue the mice from this immune checkpoint inhibitor-caused mortality.
