Hormonal therapies up-regulate MANF and overcome female susceptibility to immune checkpoint inhibitor myocarditis
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 a...
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| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
2 November 2022
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| In: |
Science translational medicine
Year: 2022, Volume: 14, Issue: 669, Pages: 1-15 |
| ISSN: | 1946-6242 |
| DOI: | 10.1126/scitranslmed.abo1981 |
| Online Access: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1126/scitranslmed.abo1981 Verlag, lizenzpflichtig, Volltext: https://www.webofscience.com/api/gateway?GWVersion=2&SrcAuth=DOISource&SrcApp=WOS&KeyAID=10.1126%2Fscitranslmed.abo1981&DestApp=DOI&SrcAppSID=EUW1ED0A3CkKPTUKdji5VIGJ91SpW&SrcJTitle=SCIENCE+TRANSLATIONAL+MEDICINE&DestDOIRegistrantName=American+Association+for+the+Advancement+of+Science+%28AAAS%29 
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| Author Notes: | 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 Cheng, Bora 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 |
| Summary: | 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 beta 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 beta-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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| Item Description: | Gesehen am 25.01.2024 |
| Physical Description: | Online Resource |
| ISSN: | 1946-6242 |
| DOI: | 10.1126/scitranslmed.abo1981 |