Hormonal therapies up-regulate MANF and overcome female susceptibility to immune checkpoint inhibitor myocarditis

• Published in: Science translational medicine Vol. 14; no. 669; p. eabo1981
• Main Authors: Zhang, Yaohua, Sun, Chengcao, Li, Yajuan, Qin, Juan, Amancherla, Kaushik, Jing, Ying, Hu, Qingsong, Liang, Ke, Zhang, Zhao, Ye, Youqiong, Huang, Lisa A, Nguyen, Tina K, Egranov, Sergey D, Zhao, Zilong, Wu, Andrew, Xi, Yutao, Yao, Jun, Hung, Mien-Chie, Calin, George A, Cheng, Jie, Lim, Bora, Lehmann, Lorenz H, Salem, Joe-Elie, Johnson, Douglas B, Curran, Michael A, Yu, Dihua, Han, Leng, Darabi, Radbod, Yang, Liuqing, Moslehi, Javid J, Lin, Chunru
• Format: Journal Article
• Language: English
• Published: United States 02.11.2022
• Subjects: Animals; Estradiol - adverse effects; Estradiol - metabolism; Estrogen Receptor beta - metabolism; Estrogen Receptor beta - therapeutic use; Female; Humans; Immune Checkpoint Inhibitors; Male; Mice; Myocarditis - complications; Myocarditis - drug therapy; Myocytes, Cardiac - metabolism; Nerve Growth Factors - adverse effects; Nerve Growth Factors - metabolism
• ISSN: 1946-6242
• DOI: 10.1126/scitranslmed.abo1981

Immune checkpoint inhibitors (ICIs) have been increasingly used in combination for cancer treatment but are associated with myocarditis. Here, we report that tumor-bearing mice exhibited response to treatment with combinatorial anti-programmed cell death 1 and anti-cytotoxic T lymphocyte antigen-4 antibodies but also presented with cardiovascular toxicities observed clinically with ICI therapy, including myocarditis and arrhythmia. Female mice were preferentially affected with myocarditis compared to male mice, consistent with a previously described genetic model of ICI myocarditis and emerging clinical data. Mechanistically, myocardial tissue from ICI-treated mice, the genetic mouse model, and human heart tissue from affected patients with ICI myocarditis all exhibited down-regulation of (mesencephalic astrocyte-derived neurotrophic factor) and (heat shock 70-kDa protein 5) in the heart; this down-regulation was particularly notable in female mice. ICI myocarditis was amplified by heart-specific genetic deletion of mouse and was attenuated by administration of recombinant MANF protein, suggesting a causal role. Ironically, both and were transcriptionally induced by liganded estrogen receptor β and inhibited by androgen receptor. However, ICI treatment reduced serum estradiol concentration to a greater extent in female compared to male mice. Treatment with an estrogen receptor β-specific agonist and androgen depletion therapy attenuated ICI-associated cardiac effects. Together, our data suggest that ICI treatment inhibits estradiol-dependent expression of in the heart, curtailing the cardiomyocyte response to immune injury. This endocrine-cardiac-immune pathway offers new insights into the mechanisms of sex differences in cardiac disease and may offer treatment strategies for ICI myocarditis.