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

• DOI: 10.1126/scitranslmed.abo1981
• Publication Date: 2022-11-02T17:58:46Z
• Authors: 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
• Keywords: Male; 0301 basic medicine; Cardiovascular; Medical and Health Sciences; Mice; 03 medical and health sciences; 2.1 Biological and endogenous factors; Humans; Animals; Estrogen Receptor beta; Myocytes, Cardiac; Nerve Growth Factors; Aetiology; Immune Checkpoint Inhibitors; Myocytes; Estradiol; Biological Sciences; Estrogen; 3. Good health; [SDV] Life Sciences [q-bio]; Myocarditis; Heart Disease; 5.1 Pharmaceuticals; Female; Development of treatments and therapeutic interventions; Cardiac

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 combinatorial anti–programmed cell death 1 and anti–cytotoxic T lymphocyte antigen–4 antibodies also presented cardiovascular toxicities observed clinically ICI therapy, including myocarditis arrhythmia. Female were preferentially affected compared male mice, consistent a previously described genetic model of emerging clinical data. Mechanistically, myocardial tissue from ICI-treated the mouse model, human heart patients all down-regulation MANF (mesencephalic astrocyte–derived neurotrophic factor) HSPA5 (heat shock 70-kDa protein 5) heart; this was particularly notable female mice. amplified by heart-specific deletion Manf attenuated administration recombinant protein, suggesting causal role. Ironically, both transcriptionally induced liganded estrogen receptor β inhibited androgen receptor. However, reduced serum estradiol concentration greater extent Treatment an β–specific agonist depletion therapy ICI-associated cardiac effects. Together, our data suggest inhibits estradiol-dependent expression MANF/HSPA5 heart, curtailing cardiomyocyte immune injury. This endocrine-cardiac-immune pathway offers new insights into mechanisms sex differences disease may offer strategies