Hormonal therapies up-regulate MANF and overcome female susceptibility to immune checkpoint inhibitor myocarditis - Archive ouverte HAL
Article Dans Une Revue Science Translational Medicine Année : 2022

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

Yaohua Zhang
Chengcao Sun
Yajuan Li
Juan Qin
Kaushik Amancherla
  • Fonction : Auteur
Ying Jing
  • Fonction : Auteur
Qingsong Hu
  • Fonction : Auteur
Ke Liang
  • Fonction : Auteur
Zhao Zhang
Youqiong Ye
Lisa Huang
  • Fonction : Auteur
Tina Nguyen
  • Fonction : Auteur
Sergey Egranov
Zilong Zhao
Andrew Wu
Yutao Xi
  • Fonction : Auteur
Jun Yao
Mien-Chie Hung
George Calin
  • Fonction : Auteur
Jie Cheng
  • Fonction : Auteur
Bora Lim
Lorenz Lehmann
Douglas Johnson
  • Fonction : Auteur
Michael Curran
Dihua Yu
Leng Han
Radbod Darabi
  • Fonction : Auteur
Liuqing Yang
Javid Moslehi
Chunru Lin

Résumé

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.
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Dates et versions

hal-04002869 , version 1 (23-02-2023)

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Citer

Yaohua Zhang, Chengcao Sun, Yajuan Li, Juan Qin, Kaushik Amancherla, et al.. Hormonal therapies up-regulate MANF and overcome female susceptibility to immune checkpoint inhibitor myocarditis. Science Translational Medicine, 2022, 14 (669), ⟨10.1126/scitranslmed.abo1981⟩. ⟨hal-04002869⟩
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