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Temporal analysis of type 1 interferon activation in tumor cells following external beam radiotherapy or targeted radionuclide therapy.
Jagodinsky, Justin C; Jin, Won Jong; Bates, Amber M; Hernandez, Reinier; Grudzinski, Joseph J; Marsh, Ian R; Chakravarty, Ishan; Arthur, Ian S; Zangl, Luke M; Brown, Ryan J; Nystuen, Erin J; Emma, Sarah E; Kerr, Caroline; Carlson, Peter M; Sriramaneni, Raghava N; Engle, Jonathan W; Aluicio-Sarduy, Eduardo; Barnhart, Todd E; Le, Trang; Kim, KyungMann; Bednarz, Bryan P; Weichert, Jamey P; Patel, Ravi B; Morris, Zachary S.
Afiliação
  • Jagodinsky JC; Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI.
  • Jin WJ; Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI.
  • Bates AM; Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI.
  • Hernandez R; Department of Radiology, University of Wisconsin School of Medicine and Public Health, Madison, WI.
  • Grudzinski JJ; Department of Radiology, University of Wisconsin School of Medicine and Public Health, Madison, WI.
  • Marsh IR; Department of Medical Physics, University of Wisconsin School of Medicine and Public Health, Madison, WI.
  • Chakravarty I; Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI.
  • Arthur IS; Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI.
  • Zangl LM; Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI.
  • Brown RJ; Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI.
  • Nystuen EJ; Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI.
  • Emma SE; Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI.
  • Kerr C; Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI.
  • Carlson PM; Department of Radiology, University of Wisconsin School of Medicine and Public Health, Madison, WI.
  • Sriramaneni RN; Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI.
  • Engle JW; Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI.
  • Aluicio-Sarduy E; Department of Radiology, University of Wisconsin School of Medicine and Public Health, Madison, WI.
  • Barnhart TE; Department of Medical Physics, University of Wisconsin School of Medicine and Public Health, Madison, WI.
  • Le T; Department of Medical Physics, University of Wisconsin School of Medicine and Public Health, Madison, WI.
  • Kim K; Department of Medical Physics, University of Wisconsin School of Medicine and Public Health, Madison, WI.
  • Bednarz BP; Department of Biostatistics and Medical Informatics, University of Wisconsin School of Medicine and Public Health, Madison, WI.
  • Weichert JP; Department of Biostatistics and Medical Informatics, University of Wisconsin School of Medicine and Public Health, Madison, WI.
  • Patel RB; Department of Medical Physics, University of Wisconsin School of Medicine and Public Health, Madison, WI.
  • Morris ZS; Department of Radiology, University of Wisconsin School of Medicine and Public Health, Madison, WI.
Theranostics ; 11(13): 6120-6137, 2021.
Article em En | MEDLINE | ID: mdl-33995649
ABSTRACT
Rationale Clinical interest in combining targeted radionuclide therapies (TRT) with immunotherapies is growing. External beam radiation therapy (EBRT) activates a type 1 interferon (IFN1) response mediated via stimulator of interferon genes (STING), and this is critical to its therapeutic interaction with immune checkpoint blockade. However, little is known about the time course of IFN1 activation after EBRT or whether this may be induced by decay of a TRT source.

Methods:

We examined the IFN1 response and expression of immune susceptibility markers in B78 and B16 melanomas and MOC2 head and neck cancer murine models using qPCR and western blot. For TRT, we used 90Y chelated to NM600, an alkylphosphocholine analog that exhibits selective uptake and retention in tumor cells including B78 and MOC2.

Results:

We observed significant IFN1 activation in all cell lines, with peak activation in B78, B16, and MOC2 cell lines occurring 7, 7, and 1 days, respectively, following RT for all doses. This effect was STING-dependent. Select IFN response genes remained upregulated at 14 days following RT. IFN1 activation following STING agonist treatment in vitro was identical to RT suggesting time course differences between cell lines were mediated by STING pathway kinetics and not DNA damage susceptibility. In vivo delivery of EBRT and TRT to B78 and MOC2 tumors resulted in a comparable time course and magnitude of IFN1 activation. In the MOC2 model, the combination of 90Y-NM600 and dual checkpoint blockade therapy reduced tumor growth and prolonged survival compared to single agent therapy and cumulative dose equivalent combination EBRT and dual checkpoint blockade therapy.

Conclusions:

We report the time course of the STING-dependent IFN1 response following radiation in multiple murine tumor models. We show the potential of TRT to stimulate IFN1 activation that is comparable to that observed with EBRT and this may be critical to the therapeutic integration of TRT with immunotherapies.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Melanoma Experimental / Carcinoma de Células Escamosas / Interferon Tipo I Tipo de estudo: Prognostic_studies Idioma: En Ano de publicação: 2021 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Melanoma Experimental / Carcinoma de Células Escamosas / Interferon Tipo I Tipo de estudo: Prognostic_studies Idioma: En Ano de publicação: 2021 Tipo de documento: Article