Androgen deprivation therapy-resistant club cells are linked to myeloid cell-driven immunosuppression in the prostate tumor microenvironment

Prostate cancer treatment resistance is a significant challenge facing the field. Genomic and transcriptomic profiling have partially elucidated the mechanisms through which cancer cells escape treatment, but their relation toward the tumor microenvironment (TME) remains elusive. Here we present a comprehensive transcriptomic landscape of the prostate TME at multiple points in the standard treatment timeline employing single-cell RNA-sequencing and spatial transcriptomics. We identify prostate club cells as a key prostate epithelial cell subtype that acts as an interface between the prostate and the immune system. Club cell-enriched tissue areas have depleted androgen signaling, increased epithelial senescence and inflammatory signaling, and a resemblance to a luminal progenitor subtype found in castrated mice. Club cells are associated with increased polymorphonuclear myeloid-derived suppressor cell (PMN-MDSC) activity that has recently emerged as a viable therapeutic target. We propose that the club cells are central to understanding and overcoming prostate cancer therapy resistance. ### Competing Interest Statement The authors have declared no competing interest.