Interferon- and STING-independent induction of type I interferon stimulated genes during fractionated irradiation.

Autor: Goedegebuure RSA; Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, location VUmc, Amsterdam, The Netherlands.; Oncode Institute, Utrecht, The Netherlands., Kleibeuker EA; Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, location VUmc, Amsterdam, The Netherlands., Buffa FM; Department of Molecular Oncology, University of Oxford, Oxford, UK., Castricum KCM; Department of Radiation Oncology, Cancer Center Amsterdam, Amsterdam UMC, location VUmc, Amsterdam, The Netherlands., Haider S; Department of Molecular Oncology, University of Oxford, Oxford, UK., Schulkens IA; Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, location VUmc, Amsterdam, The Netherlands., Ten Kroode L; Department of Radiation Oncology, Cancer Center Amsterdam, Amsterdam UMC, location VUmc, Amsterdam, The Netherlands., van den Berg J; Department of Radiation Oncology, Cancer Center Amsterdam, Amsterdam UMC, location VUmc, Amsterdam, The Netherlands., Jacobs MAJM; Department of Gastroenterology, Cancer Center Amsterdam, Amsterdam UMC, location VUmc, Amsterdam, The Netherlands., van Berkel AM; Department of Gastroenterology, Noord West Ziekenhuisgroep, Alkmaar, The Netherlands., van Grieken NCT; Department of Pathology, Cancer Center Amsterdam, Amsterdam UMC, location VUmc, Amsterdam, The Netherlands., Derks S; Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, location VUmc, Amsterdam, The Netherlands.; Oncode Institute, Utrecht, The Netherlands., Slotman BJ; Department of Radiation Oncology, Cancer Center Amsterdam, Amsterdam UMC, location VUmc, Amsterdam, The Netherlands., Verheul HMW; Department of Medical Oncology, Radboud UMC, Nijmegen, The Netherlands., Harris AL; Department of Molecular Oncology, University of Oxford, Oxford, UK., Thijssen VL; Department of Radiation Oncology, Cancer Center Amsterdam, Amsterdam UMC, location VUmc, Amsterdam, The Netherlands. v.thijssen@amsterdamumc.nl.
Jazyk: angličtina
Zdroj: Journal of experimental & clinical cancer research : CR [J Exp Clin Cancer Res] 2021 May 08; Vol. 40 (1), pp. 161. Date of Electronic Publication: 2021 May 08.
DOI: 10.1186/s13046-021-01962-2
Abstrakt: Background: Improvement of radiotherapy efficacy requires better insight in the dynamic responses that occur during irradiation. Here, we aimed to identify the molecular responses that are triggered during clinically applied fractionated irradiation.
Methods: Gene expression analysis was performed by RNAseq or microarray analysis of cancer cells or xenograft tumors, respectively, subjected to 3-5 weeks of 5 × 2 Gy/week. Validation of altered gene expression was performed by qPCR and/or ELISA in multiple cancer cell lines as well as in pre- and on-treatment biopsies from esophageal cancer patients ( NCT02072720 ). Targeted protein inhibition and CRISPR/Cas-induced gene knockout was used to analyze the role of type I interferons and cGAS/STING signaling pathway in the molecular and cellular response to fractionated irradiation.
Results: Gene expression analysis identified type I interferon signaling as the most significantly enriched biological process induced during fractionated irradiation. The commonality of this response was confirmed in all irradiated cell lines, the xenograft tumors and in biopsies from esophageal cancer patients. Time-course analyses demonstrated a peak in interferon-stimulated gene (ISG) expression within 2-3 weeks of treatment. The response was accompanied by a variable induction of predominantly interferon-beta and/or -lambda, but blocking these interferons did not affect ISG expression induction. The same was true for targeted inhibition of the upstream regulatory STING protein while knockout of STING expression only delayed the ISG expression induction.
Conclusions: Collectively, the presented data show that clinically applied fractionated low-dose irradiation can induce a delayed type I interferon response that occurs independently of interferon expression or STING signaling. These findings have implications for current efforts that aim to target the type I interferon response for cancer treatment.
Databáze: MEDLINE
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