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(MCRC Non-Clinical) Assessing the impact of oxygen tension on the generation of cancer immunity

Project Description

Project summary:
The importance of T-cell immunity to cancer outcome is becoming increasingly well-recognised. Infiltration of tumours by T-cells correlates with patient survival, and immunotherapies designed to enhance T cell function, such as checkpoint blockade, have revolutionised the way in which many solid malignancies are treated. Combination with standard-of-care treatments including radiotherapy can further enhance outcome. However, tumours frequently remain unresponsive or are devoid of T-cells. Thus, understanding barriers to T cell infiltration and mechanisms of resistance to T cell killing are critical for the future development of successful anti-cancer therapies.

The tumour microenvironment (TME) displays many characteristics generally considered hostile to T-cells including low oxygen tension (hypoxia). This contributes to T-cell dysfunction via several mechanisms including the recruitment of immune suppressive populations such as tumour-associated macrophages. Paradoxically, other recent evidence indicates that hypoxia may enhance T-cell effector function, cytotoxic potential, IFN production and formation of memory populations. Therefore, the exact contribution of intra-tumoral oxygen levels to the generation of anti-cancer immunity is unclear, particularly in response to therapy.

This project will evaluate how dynamic changes in oxygen levels during radiotherapy and immunotherapy combinations influence the generation of protective T-cell immune responses. The project will utilise pre-clinical cancer models with defined immune contexture to conduct longitudinal studies on in vivo oxygen levels using MR imaging. We will correlate oxygen dynamics with T-cell infiltration, functional activation status and overall outcome. We will explore the impact of oxygen tension on the interaction of tumour antigen-specific T-cells with cancer targets, immune synapse formation and granule deposition using advanced ex vivo imaging techniques. Data from these studies will increase understanding of tumour immuno-biology and potentially inform clinical trial design and assess value of imaging oxygen tension as a biomarker to predict response to combination therapies.

Entry Requirements:
Candidates must hold, or be about to obtain, a minimum upper second class (or equivalent) undergraduate degree in a relevant subject. A related master’s degree would be an advantage. Applications from all nationalities are welcome.

Funding Notes

The Studentship will cover an annual stipend (currently at £19,000 per annum), running expenses and PhD tuition fees at UK/EU rates. Where international student fees are payable, please provide evidence within your application of how the shortfall will be covered (approximately £19,000 per annum).

The length of this project will be FOUR YEARS.

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