Theranostics 2021; 11(13):6120-6137. doi:10.7150/thno.54881 This issue Cite

Research Paper

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

Justin C. Jagodinsky1#, Won Jong Jin1#, Amber M. Bates1, Reinier Hernandez2, Joseph J. Grudzinski2, Ian R. Marsh3, Ishan Chakravarty1, Ian S. Arthur1, Luke M. Zangl1, Ryan J. Brown1, Erin J. Nystuen1, Sarah E. Emma1, Caroline Kerr1,2, Peter M. Carlson1, Raghava N. Sriramaneni1, Jonathan W. Engle2,3, Eduardo Aluicio-Sarduy3, Todd E. Barnhart3, Trang Le4, KyungMann Kim4, Bryan P. Bednarz3, Jamey P. Weichert2, Ravi B. Patel5*, Zachary S. Morris1✉*

1. Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI.
2. Department of Radiology, University of Wisconsin School of Medicine and Public Health, Madison, WI.
3. Department of Medical Physics, University of Wisconsin School of Medicine and Public Health, Madison, WI.
4. Department of Biostatistics and Medical Informatics, University of Wisconsin School of Medicine and Public Health, Madison, WI.
5. Department of Radiation Oncology, University of Pittsburgh School Hillman Cancer Center, Pittsburgh, PA.
*Co-senior authors.
#These authors contributed equally to this work.

Citation:
Jagodinsky JC, Jin WJ, Bates AM, Hernandez R, Grudzinski JJ, Marsh IR, Chakravarty I, Arthur IS, Zangl LM, Brown RJ, Nystuen EJ, Emma SE, Kerr C, Carlson PM, Sriramaneni RN, Engle JW, Aluicio-Sarduy E, Barnhart TE, Le T, Kim K, Bednarz BP, Weichert JP, Patel RB, Morris ZS. Temporal analysis of type 1 interferon activation in tumor cells following external beam radiotherapy or targeted radionuclide therapy. Theranostics 2021; 11(13):6120-6137. doi:10.7150/thno.54881. https://www.thno.org/v11p6120.htm
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Abstract

Graphic 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.

Keywords: type 1 interferon, immune susceptibility, targeted radionuclide therapy, external beam radiotherapy, checkpoint blockade


Citation styles

APA
Jagodinsky, J.C., Jin, W.J., Bates, A.M., Hernandez, R., Grudzinski, J.J., Marsh, I.R., Chakravarty, I., Arthur, I.S., Zangl, L.M., Brown, R.J., Nystuen, E.J., Emma, S.E., Kerr, C., Carlson, P.M., Sriramaneni, R.N., Engle, J.W., Aluicio-Sarduy, E., Barnhart, T.E., Le, T., Kim, K., Bednarz, B.P., Weichert, J.P., Patel, R.B., Morris, Z.S. (2021). Temporal analysis of type 1 interferon activation in tumor cells following external beam radiotherapy or targeted radionuclide therapy. Theranostics, 11(13), 6120-6137. https://doi.org/10.7150/thno.54881.

ACS
Jagodinsky, J.C.; Jin, W.J.; Bates, A.M.; Hernandez, R.; Grudzinski, J.J.; Marsh, I.R.; Chakravarty, I.; Arthur, I.S.; Zangl, L.M.; Brown, R.J.; Nystuen, E.J.; Emma, S.E.; Kerr, C.; Carlson, P.M.; Sriramaneni, R.N.; Engle, J.W.; Aluicio-Sarduy, E.; Barnhart, T.E.; Le, T.; Kim, K.; Bednarz, B.P.; Weichert, J.P.; Patel, R.B.; Morris, Z.S. Temporal analysis of type 1 interferon activation in tumor cells following external beam radiotherapy or targeted radionuclide therapy. Theranostics 2021, 11 (13), 6120-6137. DOI: 10.7150/thno.54881.

NLM
Jagodinsky JC, Jin WJ, Bates AM, Hernandez R, Grudzinski JJ, Marsh IR, Chakravarty I, Arthur IS, Zangl LM, Brown RJ, Nystuen EJ, Emma SE, Kerr C, Carlson PM, Sriramaneni RN, Engle JW, Aluicio-Sarduy E, Barnhart TE, Le T, Kim K, Bednarz BP, Weichert JP, Patel RB, Morris ZS. Temporal analysis of type 1 interferon activation in tumor cells following external beam radiotherapy or targeted radionuclide therapy. Theranostics 2021; 11(13):6120-6137. doi:10.7150/thno.54881. https://www.thno.org/v11p6120.htm

CSE
Jagodinsky JC, Jin WJ, Bates AM, Hernandez R, Grudzinski JJ, Marsh IR, Chakravarty I, Arthur IS, Zangl LM, Brown RJ, Nystuen EJ, Emma SE, Kerr C, Carlson PM, Sriramaneni RN, Engle JW, Aluicio-Sarduy E, Barnhart TE, Le T, Kim K, Bednarz BP, Weichert JP, Patel RB, Morris ZS. 2021. Temporal analysis of type 1 interferon activation in tumor cells following external beam radiotherapy or targeted radionuclide therapy. Theranostics. 11(13):6120-6137.

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