Matches in SemOpenAlex for { <https://semopenalex.org/work/W4307930342> ?p ?o ?g. }
- W4307930342 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." @default.
- W4307930342 created "2022-11-06" @default.
- W4307930342 creator A5002078440 @default.
- W4307930342 creator A5004194329 @default.
- W4307930342 creator A5005929442 @default.
- W4307930342 creator A5008794639 @default.
- W4307930342 creator A5009823602 @default.
- W4307930342 creator A5012476537 @default.
- W4307930342 creator A5013938672 @default.
- W4307930342 creator A5014033391 @default.
- W4307930342 creator A5018014617 @default.
- W4307930342 creator A5019401898 @default.
- W4307930342 creator A5024500256 @default.
- W4307930342 creator A5025067315 @default.
- W4307930342 creator A5032233254 @default.
- W4307930342 creator A5039314254 @default.
- W4307930342 creator A5040450464 @default.
- W4307930342 creator A5041786552 @default.
- W4307930342 creator A5048715916 @default.
- W4307930342 creator A5052747073 @default.
- W4307930342 creator A5053893309 @default.
- W4307930342 creator A5056177303 @default.
- W4307930342 creator A5061301296 @default.
- W4307930342 creator A5062319147 @default.
- W4307930342 creator A5064290814 @default.
- W4307930342 creator A5065861312 @default.
- W4307930342 creator A5073804583 @default.
- W4307930342 creator A5076834432 @default.
- W4307930342 creator A5079054477 @default.
- W4307930342 creator A5084505733 @default.
- W4307930342 creator A5086895898 @default.
- W4307930342 creator A5088959356 @default.
- W4307930342 creator A5090971573 @default.
- W4307930342 date "2022-11-02" @default.
- W4307930342 modified "2023-10-03" @default.
- W4307930342 title "Hormonal therapies up-regulate MANF and overcome female susceptibility to immune checkpoint inhibitor myocarditis" @default.
- W4307930342 cites W1637076176 @default.
- W4307930342 cites W1913780655 @default.
- W4307930342 cites W1969854549 @default.
- W4307930342 cites W2004389897 @default.
- W4307930342 cites W2021639611 @default.
- W4307930342 cites W2033845089 @default.
- W4307930342 cites W2035618305 @default.
- W4307930342 cites W2043115278 @default.
- W4307930342 cites W2043659942 @default.
- W4307930342 cites W2054835199 @default.
- W4307930342 cites W2062753997 @default.
- W4307930342 cites W2063264144 @default.
- W4307930342 cites W2066253321 @default.
- W4307930342 cites W2066671159 @default.
- W4307930342 cites W2073229191 @default.
- W4307930342 cites W2080629518 @default.
- W4307930342 cites W2082131679 @default.
- W4307930342 cites W2084637523 @default.
- W4307930342 cites W2104048011 @default.
- W4307930342 cites W2106587421 @default.
- W4307930342 cites W2114104545 @default.
- W4307930342 cites W2119547813 @default.
- W4307930342 cites W2124427232 @default.
- W4307930342 cites W2127715753 @default.
- W4307930342 cites W2130073289 @default.
- W4307930342 cites W2132644095 @default.
- W4307930342 cites W2138207763 @default.
- W4307930342 cites W2148254721 @default.
- W4307930342 cites W2164092182 @default.
- W4307930342 cites W2166662937 @default.
- W4307930342 cites W2170142139 @default.
- W4307930342 cites W2518536270 @default.
- W4307930342 cites W2547133566 @default.
- W4307930342 cites W2560367415 @default.
- W4307930342 cites W2572174216 @default.
- W4307930342 cites W2588305727 @default.
- W4307930342 cites W2588979027 @default.
- W4307930342 cites W2603392025 @default.
- W4307930342 cites W2607924217 @default.
- W4307930342 cites W2749073233 @default.
- W4307930342 cites W2752427962 @default.
- W4307930342 cites W2759525729 @default.
- W4307930342 cites W2761586559 @default.
- W4307930342 cites W2774291142 @default.
- W4307930342 cites W2774511679 @default.
- W4307930342 cites W2784383617 @default.
- W4307930342 cites W2789315292 @default.
- W4307930342 cites W2793167197 @default.
- W4307930342 cites W2797107996 @default.
- W4307930342 cites W2804914481 @default.
- W4307930342 cites W2891477819 @default.
- W4307930342 cites W2891536507 @default.
- W4307930342 cites W2897815318 @default.
- W4307930342 cites W2902581700 @default.
- W4307930342 cites W2913035631 @default.
- W4307930342 cites W2913202760 @default.
- W4307930342 cites W2937040730 @default.
- W4307930342 cites W2945590213 @default.
- W4307930342 cites W2955729565 @default.
- W4307930342 cites W2969473108 @default.
- W4307930342 cites W2992178629 @default.
- W4307930342 cites W3011193772 @default.
- W4307930342 cites W3037941059 @default.
- W4307930342 cites W3039415311 @default.