Immune-Mediated Effects of Microplanar Radiotherapy with a Small Animal Irradiator

Soha Bazyar; Edward Timothy O'Brien 3rd; Thad Benefield; Victoria R Roberts; Rashmi J Kumar; Gaorav P Gupta; Otto Zhou; Yueh Z Lee

doi:10.3390/cancers14010155

Immune-Mediated Effects of Microplanar Radiotherapy with a Small Animal Irradiator

Cancers (Basel). 2021 Dec 29;14(1):155. doi: 10.3390/cancers14010155.

Authors

Soha Bazyar¹, Edward Timothy O'Brien 3rd², Thad Benefield³, Victoria R Roberts⁴, Rashmi J Kumar⁵, Gaorav P Gupta⁶, Otto Zhou⁷, Yueh Z Lee^{3

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Affiliations

¹ Department of Radiation Oncology, University of Maryland, Maryland, MD 21201, USA.
² Department of Physics and Astronomy, The University of North Carolina, Chapel Hill, NC 27514, USA.
³ Department of Radiology, The University of North Carolina, Chapel Hill, NC 27514, USA.
⁴ School of Medicine, Duke University, Durham, NC 27710, USA.
⁵ Medical Scientist Training Program, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA.
⁶ Department of Radiation Oncology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA.
⁷ Department of Applied Physics Sciences, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA.
⁸ Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA.
⁹ Biomedical Research Imaging Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA.

Abstract

Spatially fractionated radiotherapy has been shown to have effects on the immune system that differ from conventional radiotherapy (CRT). We compared several aspects of the immune response to CRT relative to a model of spatially fractionated radiotherapy (RT), termed microplanar radiotherapy (MRT). MRT delivers hundreds of grays of radiation in submillimeter beams (peak), separated by non-radiated volumes (valley). We have developed a preclinical method to apply MRT by a commercial small animal irradiator. Using a B16-F10 murine melanoma model, we first evaluated the in vitro and in vivo effect of MRT, which demonstrated significant treatment superiority relative to CRT. Interestingly, we observed insignificant treatment responses when MRT was applied to Rag^-/- and CD8-depleted mice. An immuno-histological analysis showed that MRT recruited cytotoxic lymphocytes (CD8), while suppressing the number of regulatory T cells (Tregs). Using RT-qPCR, we observed that, compared to CRT, MRT, up to the dose that we applied, significantly increased and did not saturate CXCL9 expression, a cytokine that plays a crucial role in the attraction of activated T cells. Finally, MRT combined with anti-CTLA-4 ablated the tumor in half of the cases, and induced prolonged systemic antitumor immunity.

Keywords: combined radio-immunotherapy; microbeam radiation therapy; microplanar radiation therapy; spatially fractionated radiation therapy.