Determining optimal radiotherapy and immunotherapy combinations to enhance anti-tumour immunity

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Targeting the immune checkpoints of PD-1/PD-L1 and CTLA-4 has fundamentally changed our understanding of how some cancers may be treated, revealing that CD8+ tumour infiltrating lymphocyte (TIL) responses can be highly effective providing that key regulatory mechanisms are circumvented. However, despite the clinical success of these immunotherapies, the majority of patients fail to respond or develop resistance, meaning that extensive further refinement of these therapies is urgently needed. This can likely be achieved through targeting multiple immune checkpoints in combination with established interventions such as chemotherapy or radiotherapy. While an array of therapeutic combinations are now being trialled, there are a vast number of possible combinations and rationalising this remains a huge challenge. Furthermore we are lacking understanding of the dynamics of the TIL response and how this is regulated, blunting efforts to optimally target the critical pathways involved. Current studies using either patient samples or murine models assess tumour compartments in a single temporal snapshot and thus cannot address the fundamental questions of how different TILs change over time and within the tumour microenvironment. To overcome this, we have developed in vivo models that uniquely enable labelling of immune cells specifically within the tumour, thus distinguishing newly entering and resident populations and allowing the detailed assessment of how TILs change over time. This refined analysis facilitates detailed mechanistic understanding of how therapeutic interventions work in vivo. We have recently used these dynamic tumour models to dissect how anti-PD-L1 therapy impacts both newly recruited and retained CD8 T cells specifically within the tumour environment. In this project we will build on these initial studies and ask how best to use radiation and immunotherapy to drive anti-tumour immunity. To achieve this, we will bridge the research expertise of multiple leading research groups with further support from industrial experts (AstraZeneca). Together, we will investigate how radiotherapy and immune checkpoint therapies targeting PD-L1 and additional inhibitory receptors may be best combined in pre-clinical colorectal tumour models. The studentship will support development of extensive in vivo biology skills to track immune cell migration, and characterise immune cell populations and responses using a range of techniques (multi-parameter flow cytometry, RNA sequencing and transcriptomics) in the context of radiotherapy. Building on this, we will investigate how targeting immune checkpoints in combination with radiotherapy alters the tumour immune compartment with the ultimate aim of providing robust experimental evidence for optimal combinations of therapeutic interventions for cancer patients.