Journal Article

Temporal analysis of type 1 interferon activation in tumor cells following external beam radiotherapy or targeted radionuclide therapy

Kim, KyungMann, Chakravarty, Ishan, Grudzinski, Joseph J., Bednarz, Bryan P., Le, Trang, Aluicio-Sarduy, Eduardo, Arthur, Ian S., Patel, Ravi B., Barnhart, Todd E., Hernandez, Reinier, Jin, Won Jong, Zangl, Luke M., Brown, Ryan J., Sriramaneni, Raghava N., Kerr, Caroline, Nystuen, Erin J., Emma, Sarah E., Weichert, Jamey P., Morris, Zachary S., Marsh, Ian R., Carlson, Peter M., Jagodinsky, Justin C., Bates, Amber M., Engle, Jonathan W.

2021

Overview

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. 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 Y chelated to NM600, an alkylphosphocholine analog that exhibits selective uptake and retention in tumor cells including B78 and MOC2. 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 was identical to RT suggesting time course differences between cell lines were mediated by STING pathway kinetics and not DNA damage susceptibility. 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 Y-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. 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.

• Publisher: Ivyspring International Publisher Pty Ltd,Ivyspring International Publisher
• Subject: Animals / Antigen presentation / Cancer therapies / Carcinoma, Squamous Cell - immunology / Carcinoma, Squamous Cell - physiopathology / Carcinoma, Squamous Cell - radiotherapy / Cell Line, Tumor / Cloning / Combined Modality Therapy / Dose-Response Relationship, Radiation / Dosimetry / Female / Gene expression / Gene Expression Regulation, Neoplastic - radiation effects / Gene Knockout Techniques / Head & neck cancer / Head and Neck Neoplasms - pathology / Immune Checkpoint Inhibitors / Interferon Type I - biosynthesis / Interferon Type I - genetics / Interferon Type I - physiology / Lymphocytes - drug effects / Lymphocytes - radiation effects / Melanoma / Melanoma, Experimental - immunology / Melanoma, Experimental - physiopathology / Melanoma, Experimental - radiotherapy / Membrane Proteins - agonists / Membrane Proteins - deficiency / Membrane Proteins - genetics / Membrane Proteins - physiology / Metastasis / Mice / Mice, Inbred C57BL / Neoplasm Proteins - agonists / Neoplasm Proteins - physiology / Penicillin / Radiation / Radiation therapy / Radiopharmaceuticals - pharmacokinetics / Radiopharmaceuticals - therapeutic use / Research Paper / Survival analysis / Time Factors / Tumor Protein, Translationally-Controlled 1 / Tumor Stem Cell Assay / Tumors / Up-Regulation / Yttrium Radioisotopes - pharmacokinetics / Yttrium Radioisotopes - therapeutic use