Fuelling the fight—How diet shapes the immune response to leukaemia background

Chronic lymphocytic leukaemia (CLL) is a type of blood and bone marrow cancer that progresses slowly over time. It is one of the most common types of leukaemia in adults and typically occurs during or after middle age.

While many patients experience a form of CLL that grows slowly and stays stable for years without treatment, some patients develop more aggressive forms of the disease. CLL leads to an overproduction of abnormal immune cells called B lymphocytes, which can weaken the body’s ability to fight infections and attack cancer cells. Infections are one of the main causes of death in CLL patients, and current treatments often further weaken the immune system.

Additionally, many patients become resistant or intolerant to treatment, making it harder to manage the disease. There is a pressing need for new treatments that can help restore immune system function in CLL patients.

In our recent research using a patient-derived xenograft (PDX) model of CLL, we discovered that feeding mice a ketogenic diet accelerates CLL progression via a T-cell-mediated mechanism. However, the clinical relevance of these findings and the underlying molecular mechanisms induced by the ketogenic diet remain unexplored. It is possible that certain metabolites resulting from the diet could have a pro-leukaemic effect, presenting new hypotheses for investigation.

This project will utilise a PDX model of CLL, where human CLL cells are injected into immunodeficient mice lacking T, B, and NK cells. This allows us to study the behaviour of human CLLs and T cells in a living animal. The mice will be fed different diets, and we will track how the disease progresses using various laboratory techniques.

The primary goal of this project is to investigate the impact of the ketogenic diet on CLL progression, with a focus on understanding the metabolic changes that drive the disease. Specifically, we will address the key following:

• Investigate the effects of different dietary fats on immune cell function in CLL, comparing the ketogenic diet with other high-fat or low-fat diets to identify specific dietary components that influence T-cell responses.

• Assess the reversibility of ketogenic diet-induced T-cell exhaustion by transitioning mice off the ketogenic diet and evaluating whether T-cell functionality can be restored.
• Characterise the epigenetic changes in T cells induced by the ketogenic diet and determine whether these changes contribute to T-cell exhaustion and reduced anti-tumour immunity.
• Evaluate the role of the kynurenine pathway and AHR activation in the ketogenic diet-induced T-cell dysfunction and identify potential metabolic intermediates as therapeutic targets.
• Conduct a pharmacological screen of small-molecule inhibitors that target metabolic enzymes activated by the ketogenic diet to identify compounds that can restore T-cell function and inhibit CLL progression.

Identifying inhibitors that target these metabolic changes could provide a foundation for developing new treatments for CLL that work in a completely different way from current therapies, with fewer side effects.

This research will give the student working on this project hands-on experience with cutting-edge techniques, such as working with mouse models, cell cultures, and analysing data from flow cytometry and metabolomics.

The findings could also open up opportunities for collaboration with companies developing new cancer treatments.

This project could lead to the development of new, first-in-class treatments for CLL that focus on altering metabolism. This would be a game-changer for patients whose CLL no longer responds to existing treatments, providing an entirely new option for managing the disease.