Identifying features of the immune microenvironment related to lifestyle and prostate cancer progression

Abstract

Epidemiological studies assessing prostatic inflammation have reported inconsistent associations with prostate cancer risk and outcomes. Insights into localized tumour immune activity associated with fatal prostate cancer outcomes remain poorly understood. Emerging evidence suggests that modifiable lifestyle factors may influence prostate cancer progression potentially through pro-inflammatory pathways. However, characterisation of the effect on local tissue inflammation at the prostate tumour site remains underexplored. This study aimed to integrate epidemiologic, clinical, and molecular data to investigate prognostic features of the prostate tumour immune microenvironment and their associations with potentially modifiable lifestyle factors.

Three prostate cancer cohorts from the United States and Northern Ireland (UNC CSC, FASTMAN, and FIR) were included in this thesis. Digital image analysis was optimized and validated to measure intraprostatic histologic inflammation. Tumour-infiltrating lymphocytes were then quantified in segmented regions of H&E-stained tissues and immune cell types were inferred from gene expression profiling. Immune phenotypes were further characterized via a 6-plex immunofluorescence assay. Self-reported lifestyle factors (e.g. BMI, physical activity) were assessed using structured questionnaires.

First, positive associations were identified between histologic inflammation and biochemical recurrence of prostate cancer in UNC CSC and FASTMAN cohorts. Enrichment of immunosuppressive T cell subsets, such as T-regulatory cells and exhausted CD4+ T cells, along with potential tumour-associated macrophages (estimated by gene expression) were associated with increased risk of biochemical recurrence. These associations were observed only in men with ERG-positive tumours. Further investigation in FIR supported these findings. Lastly, analysis of lifestyle factors in UNC CSC revealed that men engaged in vigorous recreational activity had reduced prostate inflammation, characterized by lower levels of exhausted CD4+ T cells and macrophages.

In conclusion, this study highlights the potential for immune phenotyping in prostate cancer risk stratification. It also provides novel evidence that modifiable lifestyle factors, especially physical activity, may alter the immune landscape of prostate tumours. These findings underscore the potential of lifestyle modification in improving immunosuppressive tumour microenvironment in prostate cancer and inform future strategies for personalized, immune-based interventions.

Thesis is embargoed until 31 December 2026.

Date of Award	Dec 2025
Original language	English
Awarding Institution	Queen's University Belfast
Sponsors	Queen's University & China Scholarship Council
Supervisor	Emma Allott (Supervisor), Melissa LaBonte Wilson (Supervisor) & Stephanie Craig (Supervisor)