PhD Studentship: Enhancing CD8+ T Cell Recruitment and Tumour Clearance via 11β-HSD1 Inhibition

Triple-negative breast cancers (TNBC) are an aggressive subtype with limited therapeutic options, where chemotherapy remains the first-line treatment. However, TNBC demonstrates high levels of resistance and metastasis, leading to poor patient outcomes. In response to chemotherapy, tumour-associated macrophages (TAMs) play a critical role in shaping the tumour microenvironment. Initial inflammatory activation of these macrophages towards an M1-like pro-inflammatory phenotype supports tumour clearance secondary to recruitment and activation of cytotoxic CD8+ T cells. However, a progressive shift towards a tolerogenic M2-like pro-resolving state limits anti-tumour immunity and instead contributes to tumour chemotherapy resistance through secretion of growth factors and inhibition of cell death pathways.

Endogenous glucocorticoids (GCs), such as cortisol, promote tolerogenic M2-like macrophage polarisation in the tumour microenvironment. The enzyme 11β-hydroxysteroid dehydrogenase-type 1 (11β-HSD1) is a glucocorticoid activating enzyme that is upregulated in inflamed tumours. We have previously shown that it functions to amplify GCs signalling in macrophages and promotes M2-like macrophage polarisation in vivo. This project explores the selective inhibition of 11β-HSD1 during chemotherapy to block drug resistance mediated by tolerogenic M2-like polarisation, and enhance M1-like inflammatory macrophage CD8+ T cell tumour-clearance.
Therefore, we hypothesise that combining 11β-HSD1 inhibitors with chemotherapy will create a synergistic effect, boosting chemotherapy’s efficacy by increasing immune-mediated tumour clearance, and preventing tolerogenic macrophage mediated chemotherapy resistance. Thus, this approach represents a novel strategy for improving outcomes in TNBC.

Objectives:

• Investigate the role of 11β-HSD1 inhibition in modulating macrophage polarisation in the tumour microenvironment.
• Assess the impact of 11β-HSD1 inhibition on CD8+ T cell recruitment, activation, and chemotherapy resistance in TNBC models.
• Determine how 11β-HSD1 inhibition affects tumour burden, metastasis, and chemotherapy efficacy in preclinical TNBC models.

This project complies with BBSRC’s emphasis on multidisciplinary research by integrating immunology, oncology, and endocrinology to investigate 11β-HSD1 inhibition in cancer therapy. It utilises advanced molecular biology techniques, animal models, and flow cytometry, fostering collaboration across fields. By combining cancer biology with immune-modulation approaches, the project also exemplifies new ways of working aimed at developing innovative bio-based solutions to enhance chemotherapy in breast cancer.

Funding notes:

For details on the BBSRC funding available for this application, please contact the main supervisor r.hardy@bham.ac.uk. Also, please check https://www.birmingham.ac.uk/research/activity/mibtp for further funding information.

References:

Melo, P. et al. (2023). Inhibition of 11β-HSD1 Enhances Chemotherapy Efficacy in Breast Cancer. Journal of Experimental Oncology. PMID: 37028818

Poinot, D. et al. (2024). Modulation of Macrophage Polarization by 11β-HSD1 Inhibitors in Immune Checkpoint Therapy. Nature Cancer. PMID: 38170044

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