T cells struggle to squeeze through stiff breast tumours, and a protein called WNK1 may be the key to why. Cytotoxic T cells must change shape and size to migrate through dense tumour tissue and latch onto cancer cells, but the mechanical forces inside stiff tumours can overwhelm them. The researchers have discovered that WNK1, previously known only for its role in kidney salt regulation, is essential for T cells to alter their shape. T cells lacking WNK1 remain tiny and rigid, unable to function. This project will test how two components of tumour stiffness—fluid pressure and mechanical stress from growing cancer cells—separately impair T cell shape changes and killing ability. Understanding this mechanical barrier could reveal why some cancers resist immunotherapy. If WNK1 or related pathways can be targeted with drugs, it might become possible to restore T cell mobility inside stiff tumours, improving the body’s natural ability to fight cancer. The work is fundamental cell biology, but it addresses a concrete physical obstacle that limits how well immune cells can do their job.
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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 insight into how stiff tumour tissues affect T cell-dependent anti-cancer responses. Furthermore, it may help to develop drugs that can either inhibit or enhance the function of T cells and will therefore impact on developing treatments against cancer.
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