ORIGINAL ARTICLE   

Journal of Neurosurgical Sciences 2023 February;67(1):55-65

DOI: 10.23736/S0390-5616.20.05060-2

Copyright © 2020 EDIZIONI MINERVA MEDICA

language: English

Radiation dose-escalation and dose-fractionation modulate the immune microenvironment, cancer stem cells and vasculature in experimental high-grade gliomas

Matteo RIVA ^{1, 2} ✉, Roxanne WOUTERS ¹, David NITTNER ³, Jolien CEUSTERS ¹, Edmond STERPIN ⁴, Roberto GIOVANNONI ⁵, Uwe HIMMELREICH ⁶, Willy GSELL ⁶, Marc VAN RANST ⁷, An COOSEMANS ^{1, 8}

¹ Laboratory of Tumor Immunology and Immunotherapy, Department of Oncology, Catholic University of Leuven, Leuven, Belgium; ² Department of Neurosurgery, UcL Namur, Mont-Godinne University Hospital, Yvoir, Belgium; ³ Center for the Biology of Disease, Catholic University of Leuven Center for Human Genetics - InfraMouse, VIB, Catholic University of University of Leuven, Leuven, Belgium; ⁴ Laboratory of Experimental Radiotherapy, Department of Oncology, Catholic University of Leuven, Leuven, Belgium; ⁵ Department of Biology, University of Pisa, Pisa, Italy; ⁶ Biomedical MRI, Department of Imaging and Pathology and Molecular Small Animal Imaging Center (MoSAIC), Catholic University of Leuven, Leuven, Belgium; ⁷ Laboratory for Clinical and Epidemiological Virology, Rega Institute for Medical Research, KU Leuven, Leuven, Belgium; ⁸ Department of Gynecology and Obstetrics, Leuven Cancer Institute, UZ Leuven, Leuven, Belgium

BACKGROUND: In the context of high-grade gliomas (HGGs), very little evidence is available concerning the optimal radiotherapy (RT) schedule to be used in radioimmunotherapy combinations. This studied was aimed at shedding new light in this field by analyzing the effects of RT dose escalation and dose fractionation on the tumor microenvironment of experimental HGGs.
METHODS: Neurospheres (NS) CT-2A HGG-bearing C57BL/6 mice were treated with stereotactic RT. For dose-escalation experiments, mice received 2, 4 or 8 Gy as single administrations. For dose-fractionation experiments, mice received 4 Gy as a single fraction or multiple (1.33x3 Gy) fractions. The impact of the RT schedule on murine survival and tumor immunity was evaluated. Modifications of glioma stem cells (GSCs), tumor vasculature and tumor cell replication were also assessed.
RESULTS: RT dose-escalation was associated with an improved immune profile, with higher CD8⁺ T cells and CD8⁺ T cells/regulatory T cells (Tregs) ratio (P=0.0003 and P=0.0022, respectively) and lower total tumor associated microglia/macrophages (TAMs), M2 TAMs and monocytic myeloid derived suppressor cells (mMDSCs) (P=0.0011, P=0.0024 and P<0.0001, respectively). The progressive increase of RT dosages prolonged survival (P<0.0001) and reduced tumor vasculature (P=0.069), tumor cell proliferation (P<0.0001) and the amount of GSCs (P=0.0132 or lower). Compared to the unfractionated regimen, RT dose-fractionation negatively affected tumor immunity by inducing higher total TAMs, M2 TAMs and mMDSCs (P=0.0051, P=0.0036 and P=0.0436, respectively). Fractionation also induced a shorter survival (P=0.0078), a higher amount of GSCs (P=0.0015 or lower) and a higher degree of tumor cell proliferation (P=0.0003).
CONCLUSIONS: This study demonstrates that RT dosage and fractionation significantly influence survival, tumor immunity and GSCs in experimental HGGs. These findings should be taken into account when aiming at designing more synergistic and effective radio-immunotherapy combinations.

KEY WORDS: Glioma; Radiotherapy; Radiation dosage; Radiation dose fractionation; Stem cells