Tumour-Immune Cell Dynamics - Withers Group
- Withers Group
Our research is focused upon understanding how immune cells adapt to, and are changed by tissues, particularly the tumour microenvironment. Deciphering this can resolve the cellular interactions and molecular mechanisms that curtail anti-tumour immunity and need to be targeted to enhance anti-cancer responses.
Tumours exploit an array of mechanisms to subvert and blunt the efforts of the host immune cells tasked with eliminating them. This impaired host immunity is a fundamental characteristic of established tumours and represents the key reason why tumours continue to grow. However, the breakthrough of cancer immunotherapy demonstrates that this immune dysfunction need not be permanent and furthermore, it is possible to block or reverse the loss of function and enhance anti-tumour responses.
However, despite the clear potential of these treatments, most cancer patients fail to durably respond. Furthermore, for some cancer types, immunotherapies have made very little impact to date. This lack of success largely reflects the multiple mechanisms within the tumour microenvironment that inhibit immune cells, frequently operating in concert. The principle aim of our research is to decipher precisely how different immune cells respond to the tumour microenvironment, why they become dysfunctional and how these changes can be corrected. Leveraging this understanding, we seek to rationalise therapy combinations able to revitalise anti-tumour responses, anticipating cancer stage- and tissue-specific treatments are necessary.
Key to our research are novel in vivo approaches that enable precise tracking of immune cell dynamics in vivo. In recent years we have pioneered models that enable temporal labelling of cells within different tissue compartments including the tumour and tumour draining lymph nodes. This methodology has helped us define the phenotype of different immune cells as they enter the tumour and crucially, how they change over time within the tissue. Recent studies have revealed rapid changes to lymphocyte effector functions soon after tumour entry as well as new insight into how tumours retain key immune populations. An array of other in vivo models and approaches complement our photolabeling experiments and enable us to test the role of specific cell types and mechanisms.
Funded through a Cancer Research UK Programme, much of our current research is focused on colorectal cancer, an extremely common cancer type which lacks adequate treatments for most patients with late-stage disease. Thus, using sophisticated in vivo models of colorectal cancer, we are now investigating the mechanisms that drive impaired T cell responses in primary and metastatic colorectal cancer.
Alongside this, as part of a Wellcome Discovery Award, we are exploring how tertiary lymphoid structures influence the anti-tumour response, again exploiting tractable in vivo models to test specific cellular interactions and functions. Working closely with the laboratories of Sophie Acton and Menna Clatworthy, we seek to define the mechanisms that regulate tertiary lymphoid structure development and define the specific roles these cellular aggregates support.
Collectively, our fundamental immunology studies will build a deep understanding of the mechanisms within the tumour microenvironment that curtail or support anti-tumour immunity. Utilising this insight we will investigate how best to manipulate these pathways to enhance anti-cancer responses, informing the design of superior treatments for patients.
Our team
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David Withers
Group Leader in Experimental Cancer Immunology
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Lisa Vettore
Postdoctoral Scientist
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Nabina Pun
Postdoctoral Scientist
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Pascale Wehr
Postdoctoral Scientist
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Ioannis Guida
Research Assistant
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Charlotte Lettau
DPhil student
