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

Yaohua Zhang, Chengcao Sun, Yajuan Li, Juan Qin, Kaushik Amancherla, Ying Jing, Qingsong Hu, Ke Liang, Zhao Zhang, Youqiong Ye, Lisa A. Huang, Tina K. Nguyen, Sergey D. Egranov, Zilong Zhao, Andrew Wu, Yutao Xi, Jun Yao, Mien Chie Hung, George A. Calin, Jie ChengBora Lim, Lorenz H. Lehmann, Joe Elie Salem, Douglas B. Johnson, Michael A. Curran, Dihua Yu, Leng Han, Radbod Darabi, Liuqing Yang, Javid J. Moslehi, Chunru Lin

Research output: Contribution to journalArticlepeer-review

3 Scopus citations


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 MANF (mesencephalic astrocyte–derived neurotrophic factor) and HSPA5 (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 Manf and was attenuated by administration of recombinant MANF protein, suggesting a causal role. Ironically, both MANF and HSPA5 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 MANF/HSPA5 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.

Original languageEnglish (US)
Article numbereabo1981
JournalScience translational medicine
Issue number669
StatePublished - Nov 2 2022

ASJC Scopus subject areas

  • Medicine(all)


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