Molecular characterization of type I IFN-induced cytotoxicity in bladder cancer cells reveals biomarkers of resistance

Although anti-tumor activities of type I interferons (IFNs) have been recognized for decades, the molecular mechanisms contributing to clinical response remain poorly understood. The complex functions of these pleiotropic cytokines include stimulation of innate and adaptive immune responses against...

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Autores principales:	Jennifer L. Green, Robin E. Osterhout, Amy L. Klova, Carsten Merkwirth, Scott R.P. McDonnell, Reza Beheshti Zavareh, Bryan C. Fuchs, Adeela Kamal, Jørn S. Jakobsen
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2021
Materias:	type I interferon bladder cancer constitutive ISG IFN resistance IFN biomarker nadofaragene firadenovec Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/3bdba8d9baec4171a65be46af11a81fb
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spelling	oai:doaj.org-article:3bdba8d9baec4171a65be46af11a81fb2021-12-02T05:02:12ZMolecular characterization of type I IFN-induced cytotoxicity in bladder cancer cells reveals biomarkers of resistance2372-770510.1016/j.omto.2021.11.006https://doaj.org/article/3bdba8d9baec4171a65be46af11a81fb2021-12-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S2372770521001558https://doaj.org/toc/2372-7705Although anti-tumor activities of type I interferons (IFNs) have been recognized for decades, the molecular mechanisms contributing to clinical response remain poorly understood. The complex functions of these pleiotropic cytokines include stimulation of innate and adaptive immune responses against tumors as well as direct inhibition of tumor cells. In high-grade, Bacillus Calmette-Guérin (BCG)-unresponsive non-muscle-invasive bladder cancer, nadofaragene firadenovec, a non-replicating adenovirus administered locally to express the IFNα2b transgene, embodies a novel approach to deploy the therapeutic activity of type I IFNs while minimizing systemic toxicities. Deciphering which functions of type I IFN are required for clinical activity will bolster efforts to maximize the efficacy of nadofaragene firadenovec and other type I IFN-based therapies, and inform strategies to address resistance. As such, we characterized the phenotypic and molecular response of human bladder cancer cell lines to IFNα delivered in multiple contexts, including adenoviral delivery. We found that constitutive activation of the type I IFN signaling pathway is a biomarker for resistance to both transcriptional response and direct cytotoxic effects of IFNα. We present several genes that discriminate between sensitive and resistant tumor cells, suggesting they should be explored for utility as biomarkers in future clinical trials of type I IFN-based anti-tumor therapies.Jennifer L. GreenRobin E. OsterhoutAmy L. KlovaCarsten MerkwirthScott R.P. McDonnellReza Beheshti ZavarehBryan C. FuchsAdeela KamalJørn S. JakobsenElsevierarticletype I interferonbladder cancerconstitutive ISGIFN resistanceIFN biomarkernadofaragene firadenovecNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENMolecular Therapy: Oncolytics, Vol 23, Iss , Pp 547-559 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	type I interferon bladder cancer constitutive ISG IFN resistance IFN biomarker nadofaragene firadenovec Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	type I interferon bladder cancer constitutive ISG IFN resistance IFN biomarker nadofaragene firadenovec Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Jennifer L. Green Robin E. Osterhout Amy L. Klova Carsten Merkwirth Scott R.P. McDonnell Reza Beheshti Zavareh Bryan C. Fuchs Adeela Kamal Jørn S. Jakobsen Molecular characterization of type I IFN-induced cytotoxicity in bladder cancer cells reveals biomarkers of resistance
description	Although anti-tumor activities of type I interferons (IFNs) have been recognized for decades, the molecular mechanisms contributing to clinical response remain poorly understood. The complex functions of these pleiotropic cytokines include stimulation of innate and adaptive immune responses against tumors as well as direct inhibition of tumor cells. In high-grade, Bacillus Calmette-Guérin (BCG)-unresponsive non-muscle-invasive bladder cancer, nadofaragene firadenovec, a non-replicating adenovirus administered locally to express the IFNα2b transgene, embodies a novel approach to deploy the therapeutic activity of type I IFNs while minimizing systemic toxicities. Deciphering which functions of type I IFN are required for clinical activity will bolster efforts to maximize the efficacy of nadofaragene firadenovec and other type I IFN-based therapies, and inform strategies to address resistance. As such, we characterized the phenotypic and molecular response of human bladder cancer cell lines to IFNα delivered in multiple contexts, including adenoviral delivery. We found that constitutive activation of the type I IFN signaling pathway is a biomarker for resistance to both transcriptional response and direct cytotoxic effects of IFNα. We present several genes that discriminate between sensitive and resistant tumor cells, suggesting they should be explored for utility as biomarkers in future clinical trials of type I IFN-based anti-tumor therapies.
format	article
author	Jennifer L. Green Robin E. Osterhout Amy L. Klova Carsten Merkwirth Scott R.P. McDonnell Reza Beheshti Zavareh Bryan C. Fuchs Adeela Kamal Jørn S. Jakobsen
author_facet	Jennifer L. Green Robin E. Osterhout Amy L. Klova Carsten Merkwirth Scott R.P. McDonnell Reza Beheshti Zavareh Bryan C. Fuchs Adeela Kamal Jørn S. Jakobsen
author_sort	Jennifer L. Green
title	Molecular characterization of type I IFN-induced cytotoxicity in bladder cancer cells reveals biomarkers of resistance
title_short	Molecular characterization of type I IFN-induced cytotoxicity in bladder cancer cells reveals biomarkers of resistance
title_full	Molecular characterization of type I IFN-induced cytotoxicity in bladder cancer cells reveals biomarkers of resistance
title_fullStr	Molecular characterization of type I IFN-induced cytotoxicity in bladder cancer cells reveals biomarkers of resistance
title_full_unstemmed	Molecular characterization of type I IFN-induced cytotoxicity in bladder cancer cells reveals biomarkers of resistance
title_sort	molecular characterization of type i ifn-induced cytotoxicity in bladder cancer cells reveals biomarkers of resistance
publisher	Elsevier
publishDate	2021
url	https://doaj.org/article/3bdba8d9baec4171a65be46af11a81fb
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Molecular characterization of type I IFN-induced cytotoxicity in bladder cancer cells reveals biomarkers of resistance

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