Understanding the role of γδ T cells in colorectal cancer
Session type: Poster / e-Poster / Silent Theatre session
Colorectal cancer is the second most common cause of cancer death in the United Kingdom. Molecular analyses indicate that colorectal cancers can be divided into four biologically distinct consensus molecular subtypes (CMS). The aim of our studies is to investigate the role of γδ T cells in each of these CMS using genetically engineered mouse models. γδ T cells account for 50-60% of T cells in the small intestine where they monitor stressed or transformed epithelial cells. However, it is largely unknown how these cells function during colorectal cancer progression.
To address this question, we first used a colitis-associated cancer model in which the loss of the tumour suppressor gene, Apc, is combined with an inflammatory agent, dextran sodium sulphate (DSS). Villin-CreER;ApcF/+ mice were crossed with γδ T cell-deficient (Tcrd—/—) mice to generate cohorts of Villin-CreER;ApcF+/;Tcrd—/— mice and Villin-CreER;ApcF+/;Tcrd+/— mice. These cohorts were treated with DSS and tamoxifen to induce bowel tumours in the presence or absence of γδ T cells.
We found that tumour incidence and tumour growth are independent of γδ T cells in this colitis model. Current efforts are underway to determine whether γδ T cells are important in models representing CMS3 (Villin-CreER;ApcF+/;KrasG12D mice) and CMS4 (Villin-CreER;KrasG12D;Trp53F/F;Nicd1LSL/+ mice) colorectal cancers. We also investigate the BTNL1-Vγ7 axis in tumourigenesis and we have found that Btnl1 mRNA expression is lost in these different CMS models.
Together, these studies may provide new opportunities for γδ T cell-based immunotherapy in colorectal cancer patients.