Study of the immunomodulatory effects of radiation therapy in solid cancers

© 2020 Joseph Ikin SiaRadiation therapy (RT) has evolved over more than a century into a well-established, highly sophisticated and major cancer treatment modality today. A paradigm shift that has occurred within the last two decades is the growing understanding that RT can induce host immune responses that contribute to tumour control, beyond direct radiation-induced cytotoxicity. Contemporaneously, the advent of modern cancer immunotherapy such as immune checkpoint inhibitors has revolutionised the field of oncology and highlighted the potential of harnessing the immune system to suppress and eradicate tumours. Inevitably, resistance to cancer immunotherapy has also brought into focus immunological barriers that preclude cancer immunity. In this context, an increasing body of pre-clinical and clinical studies substantiate the use of RT as a unique candidate to complement cancer immunotherapy in non-overlapping mechanisms to overcome such barriers. However, instruction on the optimal integration of RT and cancer immunotherapy is scarce. For the radiation oncologist, an outstanding gap in knowledge is how radiation dose-fractionation influences the immunomodulatory effects of RT and its synergy with cancer immunotherapy. In this PhD project, mouse models of solid cancer were used to systematically interrogate this question by employing a series of rationally selected radiation dose-fractionation regimens to dissect the immunological impact of dose per fraction (DPF) from that of total dose, as represented by biological effective dose (BED). In orthotopic AT3-OVA mammary carcinomas, radiation-induced CD8+ T cell responses were found to be regulated by radiation DPF, rather than BED. By contrast, radiation-induced natural killer (NK) cell responses in the same tumours were independent of radiation DPF but required a sufficient BED. Mechanistic investigations examining the cellular and transcriptional changes in AT3-OVA tumours evoked by radiation demonstrated that the differential regulation of anti-tumour immune responses by radiation DPF and BED was not primarily dictated by differences in tumour cell-intrinsic immunogenicity, but rather by the effector and suppressor dynamics in the tumour immune microenvironment, of which regulatory T cells played a central role. Furthermore, cross-examination of subcutaneously implanted MC38 colon carcinomas and publicly available transcriptomic data of human cancers pre- and post-RT suggested that radiation-induced immune responses are also significantly shaped by the tumour type. Lastly, the impact of radiation dose-fractionation on the anti-tumour activity of immune checkpoint inhibitors targeting the adaptive and innate immune arms was examined in AT3-OVA tumours, confirming the corollary that RT and immune checkpoint inhibitors do not universally synergise, but require selection of radiation regimens and checkpoint targets that are predicated on biological rationale. Overall, this PhD project represents a comprehensive side-by-side pre-clinical study of the effects of radiation dose-fractionation on host anti-tumour immune responses. Results presented herein contribute towards a clearer understanding of this complex and clinically urgent question. More broadly, insights from this project will help guide the refashioning of RT into an exciting key adjunct in the immuno-oncology era