Androgen Deprivation Therapy Drives a Distinct Immune Phenotype in Localized Prostate Cancer

Abstract Purpose: Androgen deprivation therapy (ADT) remains the backbone of prostate cancer treatment. Beyond suppression of testosterone and tumor cell growth, emerging evidence suggests ADT also modulates the immune tumor microenvironment (TME). However, a more precise understanding of the timing and intricacies of these immunological shifts is needed. Experimental Design: Here we analyzed 49 primary prostate cancers, comparing those surgically removed either without treatment or following treatment with degarelix at 4, 7, and 14 days pre-surgery. Utilizing next-generation DNA and RNA sequencing, and multiplexed immunofluorescence, we examined alterations in immune phenotypes in the presence or absence of ADT. Results: Our findings reveal that ADT rapidly transforms the typically bland prostate TME into an inflamed environment within days. Notably, we observed an increase in activated CD8 T-cells along with an increase in suppressive regulatory T-cells (Tregs). We also found an expansion of the myeloid compartment, particularly pro-inflammatory M1-like tumor-associated macrophages. Intriguingly, discernable changes which have not previously been described also occurred in tumor cells, including upregulation of antigen presentation by MHC class I and II and, unexpectedly, a decrease in the “don’t eat me” signal CD47. Conclusions: These observations underscore the critical role of timing and disease context in order to optimize the therapeutic efficacy of immune modulators combined with androgen ablation, for which the presurgical neoadjuvant setting may be ideal. Our findings warrant future prospective validation, which is currently underway.