Abstract
BackgroundImprovement 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.MethodsGene 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.ResultsGene 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.ConclusionsCollectively, 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.
Highlights
Improvement of radiotherapy efficacy requires better insight in the dynamic responses that occur during irradiation
Given the current insights in radiotherapy-induced type I interferon signaling [14, 15], as well as previous clinical trials on the combination of radiotherapy with type I interferons in cancer [16], we further focused our research on this particular response
Since the induction of a type I interferon response during radiotherapy has been linked to Cyclic GMP-AMP Synthase (cGAS)/Stimulator of interferon genes (STING) signaling [14, 20, 21], we further evaluated the role of STING as well as of interferon expression on the induction of interferon-stimulated gene (ISG) during fractionated irradiation
Summary
Improvement of radiotherapy efficacy requires better insight in the dynamic responses that occur during irradiation. Better insight in the biological and cellular response mechanisms to RTx has instigated the development of combination treatments that further improved the therapeutic outcome [2,3,4]. Many of the combination therapies comprise drugs that target tumor cell response mechanisms involved in radiotolerance or radioresistance [5, 6]. The efficacy of such combination therapies depends on adequate dosescheduling and timing of the different treatment modalities [6]. Exploring molecular responses to irradiation has been recognized as an unmet need to develop rational approaches of combination radiotherapies [6]
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