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Mechanistic Role of Steroid Metabolism in Macrophage Polarisation and CD8+ T Cell Recruitment in the Tumour Microenvironment

Secondary Supervisor(s): Prof Clare Davies

University of Registration: University of Birmingham

BBSRC Research Themes: Integrated Understanding of Health (Ageing, Pharmaceuticals)

Project Outline

Project Rationale

Tumour-associated macrophages (TAMs) play a central role in shaping the tumour microenvironment through their ability to polarise between pro-inflammatory (M1-like) and tolerogenic (M2-like) states. This balance governs the recruitment and activation of cytotoxic CD8+ T cells and ultimately determines whether tumours are controlled or progress. Endogenous glucocorticoids (GCs) are important regulators of this process, promoting M2-like polarisation. The availability of GCs is highly dependent on local metabolism and activation of steroids that in turn amplify signalling within macrophages. We have shown that steroid metabolism is induced in inflammatory microenvironments functioning as a switch towards an M2-like phenotype. This raises the possibility that local metabolism acts as a key mechanistic regulator of immune balance in tumours by limiting CD8+ T cell recruitment and anti-tumour immune responses.

Objectives

1. Define the mechanistic role of steroid metabolism in macrophage polarisation under inflammatory and stress-induced settings.

2. Investigate how macrophage steroid metabolism influences CD8+ T cell recruitment and activation in co-culture models of the tumour microenvironment.

3. Establish the signalling pathways and cytokine networks through which steroid metabolism shapes cross-talk between macrophages, tumour cells, and T cells.

Approach and Impact

The project will use human macrophage cultures, tumour co-culture systems, and functional assays including cytokine profiling, T cell migration, and pathway analysis to uncover how steroid metabolism shapes immune鈥搕umour interaction. By linking molecular events in steroid activation to immune behaviour, this work will provide mechanistic insight into macrophage plasticity and CD8+ T cell biology in inflamed tissues.