Decoding Immune Suppression in Prostate Tumors via Single-Cell and Spatial Transcriptomic Analysis

Introduction

Prostate cancer (PCa) is a heterogeneous disease, its recurrence and development of metastasis remain clinical problems. Taghreed et al. (2023) combined scRNAseq and spatial transcriptomic analyses to enhance the understanding of PCa. The data suggests that primary PCa establishes a suppressive immune microenvironment, and the prostate tumour microenvironment (TME) exhibits a high angiogenic gene expression pattern. In addition, the authors unravelled context-specific differential gene expression.

Main Points

• The TME exhibited complexity, featuring diverse subsets of myeloid cells, T-cells, NK cells, B-cells, endothelial cells, fibroblasts, and pericytes.
• The authors obtained a highly detailed spatial transcriptomics analysis detecting spatial context-dependent transcriptional differences for each cell type.
• Different epithelial subsets were identified, including hillock and club cells, which RNA velocity analysis suggested to have a progenitor role.
• An iterative strategy was used to distinguish malignant and normal luminal epithelial cells by detecting genomic aberrations, resulting in a concise ‘Prostate Tumour Gene Signature,’ which robustly identified tumour samples across independent datasets.
• Several stromal cell subpopulations and their distribution were identified. Certain endothelial and pericyte subpopulations exhibited an angiogenic signature, while fibroblasts data suggest a role in inducing extracellular matrix remodelling.
• Immunosuppressive tumour-inflammatory monocyte with high myeloid derived suppressor cells gene signature was obtained. In addition, M2-macrophages were more abundant in the TME which are involved in the growth and progression of PCa.
• No significant T-cell differences in low and high grades cases were observed, this suggests that even low grade tumours had a highly immunosuppressive TME.
• The CD56DIM NK cells were expanded in the tumour fraction which suggests a less cytotoxic activity.
• CCL20-CCR6 ligand-receptor interaction was identified and the authors showed that CCL20-blocking antibody significantly reduced tumour growth in subcutaneous models of syngeneic PCa.

Concluding Remarks

Validating the biological connections between tumours, adjacent immune and stromal cells is crucial for enhancing our comprehension of prostate cancer progression. Spatial transcriptomics preserves the tissue architecture and cell-cell interactions, and in combination with single cell sequencing will facilitate the discovery of novel therapeutic targets.

Epistem Services

Similar to the techniques outlined in this paper, Epistem regularly  employs qPCR and NGS services for gene expression, whole-exome, genotyping and epigenetic analysis from fresh, frozen and FFPE tissue.

Laser Capture Microscopy (LCM) is a powerful tool used at Epistem to select individual cells from a population in a tissue for input into downstream histochemical profiling or transcriptomic analysis.

The Histology and Immunohistochemistry team at Epistem have a wealth of experience in developing IHC protocols for a range of biological targets. Our deep understanding of IHC methodology has allowed us to develop and troubleshoot hundreds of working protocols for both automated (Ventana Discovery Ultra) and manual applications. We offer a bespoke service which could be suited to your project. We can work readily with FFPE, frozen tissues, with chromogenic and fluorescent detection systems as well as RNAScope methodologies.