Investigating The Effect Of Radiotherapy On The Tumour Microenvironment To Identify Potential Prognostic And Predictive Biomarkers Of Radiotherapy Response

Abstract

Radiotherapy (RT) plays a vital role in cancer treatment. Preclinical evidence has shown RT induces changes in tumour cells and immune cells in the tumour microenvironment (TME), potentially leading to enhanced activation of the innate immune system and priming of tumour-specific T-cell immunity. However, the impact of RT on the TME in vivo and its potential effects on tumour response to RT remain unclear. In this thesis, the local and systemic immune effects of RT on the TME and blood were investigated in patients with rectal cancer, bladder cancer, and non-small cell lung cancer (NSCLC). In rectal cancer, the longitudinal analysis from multiplex IHC revealed significant changes induced by RT in various immune cells, suggesting that RT induces immunostimulatory effects in the TME. Responders demonstrated significantly higher levels of cytotoxic T cells at baseline than non-responders. Gene sequencing analysis revealed an inflamed gene expression profile in responders and a suppressed gene expression profile in non-responders. In bladder cancer, RT induced an increase in the percentages of neutrophils (CD66b+CD14- cells) in urine samples during RT. In NSCLC, the majority of immune cells in the blood were classical monocytes, which increased during RT. The increase in PD-L1 on tumour cells may be higher in patients responding to RT. Overall, the findings suggest that RT exerts local and systemic immune effects in different cancer types, but these effects differ across cancer types. The findings are hypothesis-generating and require validation in ongoing and future clinical trials, including the TIMM-RAD study, to further develop biomarkers of immunological responses to RT. Additionally, analysis of the ILROG study data suggests that hypo-fractionated RT achieves good local control and manageable safety profiles in the treatment of haematological malignancies. This provides a rationale for further studies on reduced doses with shortened RT and demonstrates that hypo-fractionated RT is a feasible option for future health crises where limiting hospital visits may be critical. In summary, this thesis provides valuable insights into the immune effects of RT in different cancer types and highlights the need for further research to develop optimal combinations of immuno-oncology agents with RT to enhance RT responses and tumour control in the clinic.

Date of Award	1 Aug 2023
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Eleanor Cheadle (Supervisor) & Timothy Illidge (Supervisor)