Transcriptomics

Dataset Information

0

Hormonal Therapies Upregulate 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 particularly associated with myocarditis. Here, we report that tumor-bearing mice exhibited response to treatment with combinatorial anti-PD-1 (programmed cell death 1) and anti-CTLA-4 (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 as well as 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 downregulation of MANF (Mesencephalic Astrocyte Derived Neurotrophic Factor) and HSPA5 (Heat Shock 70kDa Protein 5) in the heart; this downregulation was particularly striking 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-βbeta 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 as well as androgen depletion therapy attenuated ICI-associated cardiac effects. Taken together, our data suggest that ICI treatment inhibits the 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE213468 | GEO | 2022/09/18

REPOSITORIES: GEO

Dataset's files

Source:
Action DRS
Other
Items per page:
1 - 1 of 1

Similar Datasets

2024-02-02 | GSE248625 | GEO
2023-07-01 | GSE227437 | GEO
2011-01-14 | GSE26630 | GEO
2011-01-14 | E-GEOD-26630 | biostudies-arrayexpress
2023-02-13 | GSE225099 | GEO
2024-06-20 | GSE262658 | GEO
2012-12-20 | E-GEOD-34807 | biostudies-arrayexpress
2013-12-24 | E-GEOD-53607 | biostudies-arrayexpress
2022-08-14 | GSE211096 | GEO
2012-01-19 | GSE35182 | GEO