172P - The impact of androgen ablation on the immune landscape in therapy-resistant prostate cancer: Insights from tumour microenvironment analysis

Background

Prostate cancer, the second most common cancer globally, continues to pose significant treatment challenges due to the frequent development of drug resistance. A deeper understanding of the tumour microenvironment (TME) is essential for addressing cancer progression and therapy resistance. Androgen receptor (AR) signalling is pivotal not only in tumour cells but also in the surrounding immune cells, such as tumour-associated macrophages (TAMs). This study explores the influence of the AR signalling axis on the immune landscape, particularly focusing on the crosstalk between prostate cancer cells and macrophages within the TME.

Methods

We employed co-culture systems to replicate the intricate TME, analysing the interactions between THP-1 macrophages and prostate cancer cells in vitro. Through Western blotting and RT-qPCR, we report the impact of androgen and anti-androgen therapies on macrophage phenotype, function and AR expression. By integrating a TaqMan array system coupled with coculture models, we achieved comprehensive analysis of regulatory impacts across multiple gene targets simultaneously. We further explored the influence of TAMs on prostate cancer progression through migration and EMT analysis.

Results

We demonstrate that AR signalling induces significant phenotypic changes in TAMs, fostering an immunosuppressive environment marked by the upregulation of anti-inflammatory markers (CD206, TGFβ, CD200) and the downregulation of pro-inflammatory mediators (TNFα, IL-1β). Additionally, TAMs influence the expression of key prostate cancer genes (FOXA1, TP53, MYC, HIF1α), growth factors (EGF, VEGFα), and EMT markers (TWIST, SNAIL, CTNNB1, Fibronectin), associated with enhanced tumour survival and therapy resistance. Our results suggests an immunosuppressive role of TAMs in the TME, which is influenced by androgens, enabling tumour progression.

Conclusions

This study underscores the critical role of the immune microenvironment in prostate cancer and highlights the potential of targeting TAMs in resistant disease. By identifying biomarkers and signalling pathways affected by androgen signalling, our research paves the way for novel therapeutic strategies.

Editorial acknowledgement

Clinical trial identification

Legal entity responsible for the study

The author.

Funding

Institute of Medicine, Medical Science and Nutrition, University of Aberdeen.

Disclosure

The author has declared no conflicts of interest.