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Temporal analysis of type 1 interferon activation in tumor cells following external beam radiotherapy or targeted radionuclide therapy
- Source :
- Theranostics
- Publication Year :
- 2021
- Publisher :
- Ivyspring International Publisher, 2021.
-
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.
- Subjects :
- Time Factors
medicine.medical_treatment
Melanoma, Experimental
Medicine (miscellaneous)
external beam radiotherapy
Gene Knockout Techniques
Mice
Immune system
Interferon
In vivo
Cell Line, Tumor
Animals
Medicine
Yttrium Radioisotopes
Lymphocytes
External beam radiotherapy
Immune Checkpoint Inhibitors
Pharmacology, Toxicology and Pharmaceutics (miscellaneous)
Tumor Stem Cell Assay
business.industry
Membrane Proteins
Tumor Protein, Translationally-Controlled 1
type 1 interferon
Dose-Response Relationship, Radiation
Combined Modality Therapy
targeted radionuclide therapy
Immune checkpoint
Neoplasm Proteins
Up-Regulation
Blockade
Gene Expression Regulation, Neoplastic
Mice, Inbred C57BL
Sting
Head and Neck Neoplasms
Stimulator of interferon genes
Interferon Type I
Carcinoma, Squamous Cell
Cancer research
checkpoint blockade
Female
Radiopharmaceuticals
business
immune susceptibility
Research Paper
medicine.drug
Subjects
Details
- ISSN :
- 18387640
- Volume :
- 11
- Database :
- OpenAIRE
- Journal :
- Theranostics
- Accession number :
- edsair.doi.dedup.....daed47a443e514231d36d2cbac68e4e3