Dr Seth Coffelt and Dr Kevin Myant
γδT cells are a rare population of T cell receptor-expressing cells that function like innate immune cells. γδ T cells consist of several different subtypes that can promote or prevent cancer progression, depending on the cytokines and cytotoxic molecules they express. IFNγ-producing γδ T cells are considered anti-tumorigenic cells, and the Coffelt lab has shown that these cells recognize and directly kill breast cancer cells. Conversely, the Myant lab has found that IFNγ-producing γδ T cells infiltrate tumours in mouse models of colitis associated colorectal cancer, where they promote tumour growth. This pro-tumorigenic role of IFNγ-producing γδ T cells is perpetuated by the loss of DOCK2, an activator of the actin remodelling molecule, Rac. However, how DOCK2 influences the behaviour of IFNγ-producing γδ T cells and the context in which IFNγ-producing γδ T cells can mediate pro- or anti-tumour functions remains unknown. In this project, we will explore when and where IFNγ-producing γδ T cells are tumour suppressive versus tumour stimulatory. We hypothesize that IFNγ-producing γδ T cells function differently in inflammatory-driven tumours as compared with sporadic tumours. This hypothesis will be tested in the following specific aims:
- Characterize the phenotype of IFNγ-producing γδ T cells in inflammation-driven and sporadic mouse models of colon and pancreatic cancer
- Determine how DOCK2 impacts STAT1/IRF/T-BET/IFNγ signalling in γδ T cells
- Determine the mechanism by which IFNγ-producing γδ T cells drive cancer progression.