Dr Constantinos Savva

• The comprehensive evaluation of the immunometabolic phenotype of tumour microenvironment in breast cancer.
• Investigation of the underlying biology and immunomodulatory effects of anti-PD1 and metformin combination using targeted transcriptomics and multiplex immunohistochemistry in a breast tumour murine model.

The subject of my PhD research was ‘The impact of crown-like structures (CLS) and metabolic intervention on immune responses in patients with primary breast cancer’.

My PhD research showed the presence CLS, that are macrophages encircling adipocytes, in a cohort of patients with HER2+ breast tumours was correlated to high body mass index (BMI) and poor outcomes in trastuzumab-treated patients. We also evaluated the effect of metformin on tumour-infiltrating immune cells in two independent cohorts. Metformin was associated with higher tumour-infiltrating immune cell densities and lower density of regulatory T-cells, an effect that was more prominent in patients with high BMI and elevated serum leptin. We also performed multiplexed immunohistochemistry for various immune cell markers that showed that CLS were associated with a differential effect on the densities and spatial distribution of immune cells that is tumour subtype specific. Using targeted RNA sequencing, we showed that the presence of CLS was associated with inflammatory signatures at the tumour border and an aggressive molecular phenotype in the tumour core that may promote tumour growth and immune suppression. 

Our research aims to understand and restore immune function in patients with breast cancer by investigating the role of lifestyle, exercise, body composition and metabolic parameters. Knowledge gained from this research could ultimately result in the development new treatment strategies for patients with breast cancer.