Session Item

Malignant tumours have decreased oxygenation due to malformed blood vessels. Hypoxia decreases the effectiveness of radiotherapy (RT), and the abnormal vessels prevent both systemic therapies and immune cells from reaching some areas of the tumour. Tumour hypoxia is associated with poorer prognosis. This study was aimed at quantifying alterations of the tumour microenvironment (TME) that can be achieved with varying RT fractionation. The objective was to assess changes in vasculature normalisation and reoxygenation that can be achieved with localised RT in order to facilitate better tumour access for lymphocytes and systemic therapies. 

AB1-HA mesothelioma tumour cells were subcutaneously injected into BALB/cJAusbP mice. Mice with established tumours underwent RT fractionation with an X-RAD 225Cx small animal RT device, a pre-clinical translation of clinical linear accelerators. Starting 10 days post-inoculation, mice received one of the following fractionation schedules: 0 Gy, 2 Gy x 3, 2 Gy x 4, 2 Gy x 5, 6 Gy x 1 or 6 Gy x 2 fractions. Fractions were delivered on consecutive days. On day 15 mice underwent hybrid optical and Doppler ultrasound imaging with a LAZR-X photoacoustic imaging instrument, to assess the spatial oxygen saturation concentration and the vasculature within the tumour. Imaging continued every second day, until day 29 post-inoculation, when mice were euthanised, and tumours harvested. Harvested tumours were stained for markers of vasculature and hypoxia.

Alterations to the TME were observed following different RT fractionation schedules. Imaging showed an increase in oxygen saturation and vascularisation for irradiated tumours. The changes were significant for 2 Gy x 4, 2 Gy x 5 and 6 Gy x 2 fractions compared to the control, with 2 Gy x 5 having the greatest increase and being extremely significant (p<0.1x10^-6) across all modalities. These results were supported by tissue stains, which showed both an overall absolute increase in vasculature and improved vessel normalisation.

RT fractionation can be used to modulate the TME. This has the potential to be exploited to prime the tumour for susceptibility to other treatments, for example immune checkpoint inhibitors.