Synapse - Innate immune signaling drives late cardiac toxicity following DNA-damaging cancer therapies

Innate immune signaling drives late cardiac toxicity following DNA-damaging cancer therapies Journal Article

Authors:	Shamseddine, A.; Patel, S. H.; Chavez, V.; Moore, Z. R.; Adnan, M.; Di Bona, M.; Li, J.; Dang, C. T.; Ramanathan, L. V.; Oeffinger, K. C.; Liu, J. E.; Steingart, R. M.; Piersigilli, A.; Socci, N. D.; Chan, A. T.; Yu, A. F.; Bakhoum, S. F.; Schmitt, A. M.
Article Title:	Innate immune signaling drives late cardiac toxicity following DNA-damaging cancer therapies
Abstract:	DNA-damaging cancer therapies induce delayed activation of cGAS-STING-dependent type I interferon signaling in the heart. DNA damage-induced cGAS-STING signaling drives cardiac inflammation and late pathologic remodeling of the heart, progressive cardiac functional impairment, and late lethal cardiac toxicity. Late cardiac toxicity is a potentially lethal complication of cancer therapy, yet the pathogenic mechanism remains largely unknown, and few treatment options exist. Here we report DNA-damaging agents such as radiation and anthracycline chemotherapies inducing delayed cardiac inflammation following therapy due to activation of cGAS- and STING-dependent type I interferon signaling. Genetic ablation of cGAS-STING signaling in mice inhibits DNA damage-induced cardiac inflammation, rescues late cardiac functional decline, and prevents death from cardiac events. Treatment with a STING antagonist suppresses cardiac interferon signaling following DNA-damaging therapies and effectively mitigates cardiac toxicity. These results identify a therapeutically targetable, pathogenic mechanism for one of the most vexing treatment-related toxicities in cancer survivors.
Keywords:	doxorubicin; radiotherapy; survivors; cardiotoxicity; mouse model; disease; radiation-therapy; dysfunction; heart-failure; sting pathway
Journal Title:	Journal of Experimental Medicine
Volume:	220
Issue:	3
ISSN:	0022-1007
Publisher:	Rockefeller University Press
Date Published:	2023-03-06
Start Page:	e20220809
Language:	English
ACCESSION:	WOS:000900184500001
DOI:	10.1084/jem.20220809
PROVIDER:	wos
PMCID:	PMC9767651
PUBMED:	36534085
Notes:	Article -- Source: Wos