| Summary: | <p>More than half of cancer patients receive radiotherapy in the course of their treatment. Recently, clinical and preclinical studies have indicated that radiation may have anti-cancer effects through the initiation of tumour-specific immune responses in addition to tumour cell-intrinsic DNA-damage. The role of the tumour microenvironment in cancer development, progression and response to therapy is increasingly being recognised. However, few pre-clinical models are available for the co-evaluation of tumour and normal tissues in response to radiation therapy. The aims of this thesis are: (1) to establish a pre-clinical mouse model which can be used to evaluate tumour and normal tissue responses to cancer therapies; (2) to dissect the critical biological processes in carcinogen-induced lung tumour initiation and development (with a focus on immune and stromal context); and (3) to investigate the mechanisms important in radiation-induced normal tissue responses in cardiac and lung tissues.</p>
<p>Using the A/J mouse model, we established a relevant model in which to study effects of radiation. In mice treated with the carcinogen, urethane, we found that radiation treatment during the expected period of tumour initiation resulted in fewer and smaller tumours compared with controls. In parallel, we observed increased occurrence of distinct lymphocyte aggregates in the mice that had fewer tumours, which we further confirmed were positive for markers including CD3, CD19, CD103, MHCII, CXCL13 and B220. Results from treatment with a STING agonist (DMXAA) at tumour initiation were complex, revealing a decrease in tumour numbers, but an increase in tumour burden. In established lung tumours, T-cell exclusion was observed 7 days after irradiation, along with indications of chronic inflammation occurring in the lung parenchyma. Investigation of late radiation-induced pathological events in the heart revealed an increase in fibrosis in the pericardium and perivasculature in addition to discernible changes in electrical conduction including increases in QTc and P-R intervals and variability in heart rate. Unexpectedly, we observed sustained DDR in cardiac cells that lasted up to 7 days after irradiation.</p>
<p>In conclusion, our data introduce the A/J mouse as a novel model for studying both late cardiac toxicity and anti-tumour effects following radiation using both physiological and pathological endpoints. Our results also suggest that a potential ‘vulnerable state’ may exist prior to neoplastic cell transformation after carcinogen treatment of lung cells, that might be targeted to prevent the future development of tumours. These vulnerabilities may lie the altered cell division processes or acute immune responses that are impacted by radiation. Furthermore, STING agonism may add a selection pressure during tumourigenesis, potentially resulting in the more immune-resilient clones surviving and proliferating. The relationship between the persistent DDR observed after irradiation of cardiac tissue and the late electrophysiological and pathological effects warrants further investigation.</p>
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