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

Abstract

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.

Immunosuppression for immune-related adverse events during checkpoint inhibition: an intricate balance

“…Some autoimmunity, like myocarditis, can reproducibly be induced in transgenic CTLA4 −/− or PDCD1 −/− mice 135 . In contrast to observations in humans, spontaneous irAEs, which are solely induced by immune checkpoint targeted monoclonal antibodies, are sparsely observed in rodents 133 , 136 , 137 . Therefore, inflammation is often induced by additional means in irAE experiments, either by using mice with a predisposing genetic background (such as non-obese diabetic mice), immunisation (as with experimental autoimmune encephalitis or myocarditis), irradiation or biochemical initiation of inflammation (as with DSS-induced colitis) 82 , 109 , 135 , 138 .…”

Equity in Cardio-Oncology Care and Research: A Scientific Statement From the American Heart Association

“…For example, women show differing expression of key pathways involved in the development of ICI myocarditis compared with men. 16 Because of this and the historical underrepresentation of women and racial and ethnic groups in many key trials used to inform clinical care and interpretation of risk, we suggest strong effort be made toward exploring potential biological pathways and factors (eg, gene variants) related to differences in cardiotoxic risk and disease severity. [5][6][7] These efforts will allow the tailoring of care in an era of increasing focus on precision medicine.…”

“…14 This is consistent with clinical data that some female patients may be more prone to developing ICI-associated myocarditis for unclear reasons, possibly related to estradiol-dependent pathway attenuation. 15,16 The mechanisms of sex-dependent differences and immune-related adverse effects require more investigation at the preclinical and patient levels to determine biological differences in cardiotoxicity outcomes.…”

Risk Factors for Immune Checkpoint Inhibitor–Mediated Cardiovascular Toxicities

“…A recently published study investigated the underlying mechanism behind these sex-specific differences in mice [ 62 ]. Female tumor-bearing mice treated with a combination of anti-PD-L1 and anti-CTLA-4 antibodies demonstrated more pronounced myocardial CD8 + lymphocyte infiltration than male ones.…”

“…Notably, more pronounced downregulation of Manf in females was a direct result of reduced β-estradiol levels following ICI treatment. The regulatory promotor region of Manf contains androgen- and estrogen-responsive elements, thus indicating a regulatory role of these hormones in the expression of Manf [ 62 ]. This indicates that female sex is a risk factor for developing ICI-mediated myocarditis and that future research is needed to elucidate this association for pericarditis and vasculitis.…”