Authors: Kinjal Bhadresha, Jessica L. Horner, Jessica D. Kindrick, Douglas K. Price, Cindy H. Chau, William D. Figg
Published: 2025-04-21
DOI: 10.1158/1538-7445.am2025-4002
Source: Full article
While immunotherapy has demonstrated remarkable success in other malignancies, its efficacy in prostate cancer remains limited. Organoid models, capable of recapitulating patient-specific therapeutic responses, offer a promising platform for studying tumor biology and treatment responses. However, their utility in modeling immune interactions remains underdeveloped. To address this, we established an in vitro co-culture system of tumor organoids and immune cells to investigate tumor-immune interactions and identify novel therapeutic targets for aggressive prostate cancer. Using publicly available LuCaP PDX microarray datasets (GSE199596 and GSE113743), we identified the downregulation of antigen processing and presentation (APP) pathways, indicative of immune evasion mechanisms. Moreover, our analysis revealed overexpression of macrophage-polarizing factors, such as the STAT signaling pathway, ARG1, and MALAT1, which are implicated in tumor progression, metastasis, and drug resistance. To experimentally validate these findings, we developed and optimized a macrophage co-culture model utilizing organoids derived from LuCaP167 and LuCaP167CR, effectively recapitulating distinct tumor microenvironment characteristics associated with castration resistance. We further assessed for drug response using targeted and Immunotherapeutics within this system to evaluate their therapeutic potential. This proof-of-concept study highlights the potential of this sustainable and scalable co-culture platform for studying cancer-immune interactions ex vivo. The model serves as a valuable tool for evaluating the efficacy of existing therapeutics and discovering novel agents that enhance immune responses in advanced prostate cancer.