LAUSR

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. Description ICI inhibits estradiol-induced cardiac MANF/HSPA5 expression, leading to myocarditis that could be attenuated by recombinant MANF or hormone therapy. Of myocarditis and women Inflammation of the heart muscle, or myocarditis, is an off-target effect of anticancer treatments such as immune checkpoint inhibitor (ICI) therapy. Here, Zhang et al. studied sex differences in ICI myocarditis. They observed greater T cell infiltration and cardiac dysfunction in female mice with ICI myocarditis and identified decreased MANF and HSPA5 expression in the heart. Cardiac depletion of Manf worsened ICI myocarditis, whereas recombinant MANF improved heart function. Treating cardiomyocytes derived from human induced pluripotent stem cells with estrogen or estrogen receptor β agonist induced MANF and HSPA5 expression. Treating female tumor-bearing mice with estrogen receptor β agonist during ICI treatment reduced T cell infiltration and preserved heart function. Results suggest that hormone therapy could limit ICI myocarditis by promoting the protective effects of MANF.