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
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Publicado: Elsevier 2021
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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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