Mechanobiological control of cytotoxic T cell-mediated anti-tumour responses

Cytotoxic T cells are a critical part of our immune system. They are the white blood cells responsible for detecting and destroying cancer cells. For them to function properly they first need to migrate into the cancer tissue. They then tightly attach to their targets before killing them. Tumour tissues, however, tend to be much stiffer than healthy tissue and it has previously been shown that T cells can struggle to enter stiff tumours. This increase in stiffness is due to several reasons, including the accumulation of fluids and the growth of the cancer cells themselves, which leads to fluid and mechanical stress.

Our research focuses on cytotoxic T cells and we plan to determine how fluid and mechanical stress can affect their ability to attach to and destroy cancer cells. We suspect that one critical factor is that they need to be able to rapidly change both their shape and their size. This allows them to migrate through narrow gaps in tissues and to attach to target cells to destroy them. However, if tumours are particularly stiff, such as is the case for breast cancer, we suspect that the external forces acting on T cells may be too big for them to overcome and their ability to navigate through the tumour and kill may be restricted. Of particular interest thereby is a protein called WNK1, which previously has mostly been studied for its role in salt reabsorption in the kidney. New results from our lab, show that WNK1 also has vital roles in T cells and is required for them to change their size and shape.

In this project, we will investigate how tumours stiffness affects T cell shape and size regulation and thereby their ability to destroy cancer cells, and how the two major components of tumour stiffness contribute to these processes. As T cells lacking WNK1 are very small and unable to change their shape, they will serve as a model to study what the impact of size and shape regulation is on T cell function.

The knowledge gained in this study will create...