Keaton Jones, Consultant Hepatobiliary and Pancreatic Surgeon at Oxford University Hospitals NHS Foundation Trust and Senior Clinical Researcher in the Department of Oncology at the University of Oxford, has received a Wellcome Trust Early Career Award to investigate the role of macrophage metabolism in determining therapeutic responses in pancreatic cancer.
This scheme provides support for early-career researchers leading innovative projects that aim to deliver shifts in understanding in human health. The funding will enable Mr Jones and his team to shed light on immunotherapy resistance in pancreatic cancer, a critical hurdle that, if overcome, could provide much needed new treatment options.
Pancreatic cancer remains one of the deadliest malignancies, with fewer than 5% of patients surviving beyond five years. A lack of early diagnostic tools and effective therapies means that up to 70% of patients receive no treatment at all and survival outcomes have not improved in two to three decades.
While immunotherapy has transformed the treatment landscape for many cancers, it has shown limited success in pancreatic cancer. A major barrier is the tumour’s unique microenvironment. Pancreatic tumours are surrounded by a dense, fibrotic stroma, infiltrated by large numbers of tumour-associated macrophages (TAMs). The result is a physical and immunosuppressive shield that prevents drugs and immune cells from reaching their targets and blunts the effectiveness of immunotherapies.
Overcoming this macrophage-driven immunosuppression could be key to making immunotherapies work for pancreatic cancer. Mr Jones’ project will investigate the biology of TAMs in greater depth, aiming to shed light on weaknesses that could be exploited to improve treatment responses.
Specifically, Mr Jones is interested in the metabolism of TAMs.
"The significance of cancer metabolism is widely recognised, but until recently, research has focused on tumour cells. We are now seeing that metabolism also plays a crucial role in dictating the function of immune cells." - Keaton Jones, Wellcome Trust Early Career Fellow
This field, known as immunometabolism, explores how changes in cellular metabolism shape the phenotype of immune cells. Metabolic reprogramming has been demonstrated in TAMs, which undergo substantial changes in response to hypoxia and nutrient alterations, as well as tumour-derived signals. These changes not only alter macrophage behaviour, but also affect the metabolites they release, influencing surrounding tumour cells and other immune cells. This complex metabolic dialogue likely contributes to tumour growth, immune evasion, and resistance to therapy.
A key question now is how changes in metabolic state facilitate the specialised activities of these cells – and which specific pathways drive TAMs towards an immunosuppressive versus immune-stimulatory state. A deeper understanding of the metabolic pathways involved could inform strategies to disrupt the pro-tumourigenic activity of TAMs and enhance treatment responses.
In this project, Mr Jones will use animal models of immunotherapy-resistant and immunotherapy-sensitive pancreatic cancer to define the metabolic traits of TAMs during the treatment response.
"By mapping the metabolomic profiles of macrophages and tracking how these change in response to treatment, we hope to identify drivers that can be targeted therapeutically."
Ultimately, these findings will help guide the development of strategies to make pancreatic tumours more sensitive to immunotherapy.