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Eosinophil-Associated Gene Pathways but not Eosinophil Numbers are Differentially Regulated between Synchrotron Microbeam Radiation Treatment and Synchrotron Broad-Beam Treatment by 48 Hours Postirradiation

Ibahim MJ, Yang Y, Crosbie JC, Stevenson A, Cann L, Paiva P, et al.

Radiat Res, 2016 Jan;185(1):60-8.
PMID: 26720800 DOI: 10.1667/RR14115.1

Synchrotron microbeam radiation treatment (MRT) is a preclinical radiotherapy technique with considerable clinical promise, although some of the underlying radiobiology of MRT is still not well understood. In recently reported studies, it has been suggested that MRT elicits a different tumor immune profile compared to broad-beam treatment (BB). The aim of this study was to investigate the effects of synchrotron MRT and BB on eosinophil-associated gene pathways and eosinophil numbers within and around the tumor in the acute stage, 48 h postirradiation. Balb/C mice were inoculated with EMT6.5 mouse mammary tumors and irradiated with microbeam radiation (112 and 560 Gy) and broad-beam radiation (5 and 9 Gy) at equivalent doses determined from a previous in vitro study. After tumors were collected 24 and 48 h postirradiation, RNA was extracted and quantitative PCR performed to assess eosinophil-associated gene expression. Immunohistochemistry was performed to detect two known markers of eosinophils: eosinophil-associated ribonucleases (EARs) and eosinophil major basic protein (MBP). We identified five genes associated with eosinophil function and recruitment (Ear11, Ccl24, Ccl6, Ccl9 and Ccl11) and all of them, except Ccl11, were differentially regulated in synchrotron microbeam-irradiated tumors compared to broad-beam-irradiated tumors. However, immunohistochemical localization demonstrated no significant differences in the number of EAR- and MBP-positive eosinophils infiltrating the primary tumor after MRT compared to BB. In conclusion, our work demonstrates that the effects of MRT on eosinophil-related gene pathways are different from broad-beam radiation treatment at doses previously demonstrated to be equivalent in an in vitro study. However, a comparison of the microenvironments of tumors, which received MRT and BB, 48 h after exposure showed no difference between them with respect to eosinophil accumulation. These findings contribute to our understanding of the role of differential effects of MRT on the tumor immune response.
Synchrotron microbeam radiotherapy evokes a different early tumor immunomodulatory response to conventional radiotherapy in EMT6.5 mammary tumors

Yang Y, Swierczak A, Ibahim M, Paiva P, Cann L, Stevenson AW, et al.

Radiother Oncol, 2019 04;133:93-99.
PMID: 30935588 DOI: 10.1016/j.radonc.2019.01.006

BACKGROUND: Synchrotron microbeam radiation therapy (MRT) is a new, evolving form of radiotherapy that has potential for clinical application. Several studies have shown in preclinical models that synchrotron MRT achieves equivalent tumor control to conventional radiotherapy (CRT) but with significantly reduced normal tissue damage.
METHODS: To explore differences between these two modalities, we assessed the immune cell infiltrate into EMT6.5 mammary tumors after CRT and MRT.
RESULTS: CRT induced marked increases in tumor-associated macrophages and neutrophils while there were no increases in these populations following MRT. In contrast, there were higher numbers of T cells in the MRT treated tumors. There were also increased levels of CCL2 by immunohistochemistry in tumors subjected to CRT, but not to MRT. Conversely, we found that MRT induced higher levels of pro-inflammatory genes in tumors than CRT.
CONCLUSION: Our data are the first to demonstrate substantial differences in macrophage, neutrophil and T cell numbers in tumors following MRT versus CRT, providing support for the concept that MRT evokes a different immunomodulatory response in tumors compared to CRT.

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