Understanding the role of γδ T cells in colorectal cancer


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Toshiyasu Suzuki1,Rachel Ridgeway1,Rene Jackstadt1,Joshua Leach1,Natalie Roberts2,Anett Jandke2,Adrian Hayday2,Owen Sansom1,Seth Coffelt1
1Cancer Research UK Beatson Institute,2Francis Crick Institute

Abstract

Background

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.

Method

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.

Results

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.

Conclusion

Together, these studies may provide new opportunities for γδ T cell-based immunotherapy in colorectal cancer patients.