ESTRO 2024 - Abstract Book

S5342

Radiobiology - Tumour biology

ESTRO 2024

in terms of survival at endpoint (p>0.05). However, radiotherapy increased the survival rate of the mice in the subcutaneous model when ulcerated mice were censored, albeit not significantly (median survival: 32 vs 25 days, p=0.05). Repeated tumour growth measurements in the orthotopic model were not possible, but in the subcutaneous setting, they revealed a significant decrease in the growth rate of the irradiated tumours compared to the untreated controls (p<0.05). Histologically, untreated tumours in both the orthotopic and subcutaneous models had similar morphology, displaying high stroma infiltration. In terms of TILs, the subcutaneous model hosted a significantly higher CD8 + cell number within the tumour at baseline compared to the orthotopic tumours (mean cell count per mm 2 : 995.2 vs 397.5, p<0.05). When immunohistochemical staining for cytotoxic T-cells was performed in the RT-treated tumours at endpoint, the orthotopic model showed unchanged levels of CD8 + cells compared to untreated controls (p>0.05). In contrast, the subcutaneous tumours marked a significant reduction in the tumour-infiltrating CD8 + cells in the irradiated mice, which was only true for the tumour epithelium (p<0.05), as the tumour-surrounding stroma did not show differences in the numbers of CD8 + cells (p>0.05). Peripheral blood counts in the orthotopic rectal model showed that irradiated mice had no differences in total neutrophil or monocyte counts compared to non-irradiated (p>0.05), apart from a significant increase in the peripheral lymphocytes (p<0.05). The heterotopic subcutaneous model also showed no difference in the peripheral cell counts between the irradiated and non-irradiated animals (p>0.05). To further interrogate the potential RT-related disparity in immune responses based on tumour site, bulk RNAseq analysis was performed in samples from the treated and untreated groups for comparison with the orthotopic model. These results are awaited.

Conclusion:

We describe an immunocompetent mouse model of rectal cancer, in which the role of targeted RT in the tumour microenvironment can be evaluated both in a heterotopic and an orthotopic setting. Although morphologically similar, the subcutaneous niche showed increased levels of TILs compared to the rectal site at baseline. Evidently, outside of the innate microenvironment, previously unresponsive rectal tumours display a differential response to irradiation. Histologically we demonstrated a disparity in the immune changes related to RT between the sites. Further work is required to better understand how the rectal tumour niche may impact RT response potentially through mechanisms involving the gut microbiome and the mucosal immune system.

Keywords: radiotherapy, tumour microenvironment

References:

1. Glynne-Jones R., et al. (2017) 'Rectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow up', Annals of Oncology , 28 (4), pp. 22-40.

2. Corrò, C., et al. (2021) 'Emerging Trends for Radio-Immunotherapy in Rectal Cancer', Cancers , 13 (6), pp.1374.

3. El Sissy, C., et al. (2023) 'International Validation of the Immunoscore Biopsy in Patients With Rectal Cancer Managed by a Watch-and-Wait Strategy', Journal of Clinical Oncology , pp. 1-11.