The immune system plays a vital role in defending the body against harmful substances, and to fight disease-causing changes in the body such as cancer cells. But cancer cells can adapt to their environment to survive and 'escape' the immune system by mutating and thereby avoiding recognition from immune cells. In response, the immune system adapts, creating a dynamic process whereby the immune system not only protects against cancer but also shapes emerging tumours.
Audrey Gérard, Associate Professor at the Kennedy Institute, University of Oxford explained: 'Cancer and immune landscapes coevolve, giving rise to a series of adaptations. While most studies to date have focused on addressing one side of this equation at a time, they are missing the interconnectivity of this process. We propose to view tumour escape and immune landscapes as a coordinated system, to help identify new targetable pathways for treatment. We are grateful to CRUK for funding this important research which will open up potential new opportunities to fight this disease.'
IFNy is a protein crucial for anti-tumour immunity and, as such, tumours can escape the immune system by mutating genes downstream of IFNy. The researchers propose to mimic tumour escape by inhibiting the IFNy signalling pathway in tumours and observing the remodelling of the immune cells. They hope to demonstrate not only that immune cells sense the escape, but to what extent they adapt and respond, and whether it can be leveraged as a new candidate for immunotherapy.
Fiona Powrie, Director of the Kennedy Institute said: 'I am delighted that Audrey and her team have been awarded this funding from CRUK and it is a clear endorsement of her and her research vision. With Audrey's leadership and drive there is great potential for the findings to be significant on numerous levels and across multiple cancers.'
The study, over 6 years, will be broken down into three stages using state-of-the-art sequencing and microscopy technologies at the Kennedy Institute. The first will be to explore the cellular basis of immune cell adaptation during IFNy-dependent escape. This stage will look closely at CD8 T-cells, a type of white blood cell responsible for recognising and destroying cancer cells, which have been shown to exhibit increased interest in tumour antigens in response to escape.
The second phase will explore the spatial relationship between tumour and immune landscapes to understand how localisation impacts the efficiency of the immune response towards tumour escape. Tumours often create immunosuppressive niches to limit anti-tumour responses, which might be disrupted during IFNy-dependent escape. Finally, the third stage will assess the human relevance of the findings. The consequences of mutations in the IFNy signalling pathway for response to immunotherapy has been debated. This work will help us understand how the emergence of those mutations remodels the immune response and thereby affects the overall treatment efficiency.
Audrey commented: 'Our goal is to explore strategies to tip the balance in favour of the immune system by leveraging the pathway within the cancer and immune interface, and offer better-personalised treatment in future.'
This research programme is funded by a CRUK Discovery Programme Foundation Award.