Exploring the gene expression programs that regulate tumour infiltrating gamma delta T cells

Colorectal cancer (CRC) is the second leading cause of cancer-related deaths worldwide. In 2020, more than 1.9 million new cases of colorectal cancer and more than 930,000 deaths due to colorectal cancer were estimated to have occurred worldwide. It has been predicted that by 2040 the burden of colorectal cancer will increase to 3.2 million new cases per year and 1.6 million deaths per year (a 73% increase). A major hurdle in developing new therapeutics for CRC has been a lack of understanding of the factors that contribute to persistence of tumours, despite potent anti-tumour mechanisms in the human body. One area we lack clarity on is the immune systems dysregulation in CRC. The epithelial cells of the intestine that commonly transforms into tumour cells are actively patrolled by tissue-associated immune cells, yet CRC tumours often escape their immune detection mechanisms. The immune cells that patrol and protect this epithelial barrier include specialized cells that express a T cell receptor (TCR), and termed, T cells. These T cells can respond and react to characteristic molecules that cancer cells express on their cell surface, known as antigens. However, successful tumours switch off key molecules that present these antigens, effectively evading TCR-mediated responses.

In this project, the student will study a poorly understood group of T cells, called gamma delta T cells. These gamma delta T cells are a major population that patrol the intestinal epithelium. We believe gamma delta T cells, directed by their unique gamma delta TCR are a vital avenue to redirect the immune system to target the tumour cells that evade conventional T cell immunity. The interdisciplinary crossover, fitting with the MRC DTP's remit, will expose the student to advanced cellular immunology and single cell bioinformatics techniques. In this project, the student will have access to matched blood, normal adjacent tissue (NAT) and tumour samples from patients undergoing surgery to resect CRC tumours. From these samples the student will use innovative immunological techniques to look at the gamma delta TCR interactions in extraordinary detail. We will uncover how these gamma delta TCRs are shaped in tumours and identify the underlying gene expression programs that are associated with tumour-associated gamma delta TCRs.