Tesa Severson1, Audrey Lacoste1, Arno Velds2, Marcos Da Silva Guimaraes3, Henk van der Poel4, Wilbert Zwart1, Andries Bergman4
(1) Division of Oncogenomics, Oncode Institute, Netherlands Cancer Institute, Amsterdam, Netherlands.
(2) Genomics Core Facility, Netherlands Cancer Institute, Amsterdam, Netherlands.
(3) Center for Molecular Pathology and Biobanking, Netherlands Cancer Institute, Amsterdam, Netherlands.
(4) Division of Medical Oncology, Netherlands Cancer Institute, Amsterdam, Netherlands.
In prostate cancer (PCa), Androgen Receptor (AR) is the critical driver of development and progression and thus the primary therapeutic target after locoregional treatment. Several strategies inhibit AR signaling in PCa, including Enzalutamide which binds AR inducing a conformational change that reduces downstream transcriptional activity. In a Phase II clinical trial, patients with high-risk primary PCa received Enzalutamide in the neoadjuvant setting. To better understand tumor-immune interactions and transcriptional responses to therapy, we profiled samples from these patients using spatial transcriptomics. We generated a Tissue MicroArray (TMA) slide with 97 patient sample cores (48 patients with two cores, one with a single core). From this slide, we profiled 535,908 cells with a median of 180 transcripts per cell. Cell types were annotated using a reference dataset for immune cells and fibroblasts, and tumor versus normal epithelium was pathologist-defined. Cell-type proportions showed no strong association with treatment outcomes. Spatial network analysis using T-cells, B-cells, macrophage and tumor cells revealed increased expression of genes linked to T-cell activation, proliferation and tumor biology. Using a database of ligand-receptor interactions, mapped incoming and outgoing CD99 pathway signals across T-cells, fibroblasts, macrophages, endothelial cells and tumor cells in our samples. Next, we will define differential gene expression patterns and map spatial interactions unique to tumor cells, enabling deeper insight into mechanisms driving therapeutic response.