ArticlemedRxiv : the preprint server for health sciences2026
The temporal dynamics of the immune response to neoadjuvant androgen deprivation therapy suggests a window-of-opportunity for checkpoint inhibitor therapy in prostate cancer.
Article in medRxiv : the preprint server for health sciences, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Purpose: Novel therapies to prevent lethal castration resistant prostate cancer in response to standard-of-care androgen deprivation therapy (ADT) are required. Unfortunately, most prostate cancers are "immune cold" and fail to respond to checkpoint inhibitors (CPIs). To assess whether ADT induces changes that enable more effective CPI therapy, we examined the tumor immune micro-environment (TiME) following neoadjuvant ADT (nADT). Design: Radical prostatectomy specimens from 43 nADT-treated patients were stratified into three duration groups and compared to each other and matched controls. RNA sequencing and quantitative multispectral immunofluorescence (qmIF) staining were performed to analyze transcriptomic and TiME abundance and cellular spatial relationship differences after nADT. Results: Immune and inflammatory pathways, particularly of antigen presentation and adaptive immune response, were increased, most notably in tumors receiving 3-5 months nADT. qmIF revealed a complex temporal response in the TiME, with a dramatic influx of CTLs and T-helper cells after 3-5 months of nADT. However, after 6 months nADT, M2-like tumor associated macrophages (TAMs) and Tregs were strikingly increased while CTLs decreased. Spatially, CTLs and T-helper cells, clustered near tumor cells at 3-5 months nADT, were replaced by M2-TAMs in tumors receiving ≥ 6 months of nADT. Conclusion: These data reveal the induction of a bi-phasic response in the TiME: robust CTL activation 3-5 months after nADT is initiated, followed by myeloid immunosuppression in tumors receiving prolonged nADT. This ADT-induced reprogramming of the TiME suggests a critical window of opportunity where short-duration ADT might augment CPI efficacy, converting cold into immunologically responsive tumors. Translational Relevance: Immune Checkpoint inhibitors (CPIs) have not been effective in treating most human prostate cancers. This study describes the temporal dynamics of the immune response of primary prostate cancers to neoadjuvant androgen deprivation therapy (nADT), and suggests a strategic approach to improve the efficacy of CPIs in prostate cancer. After several months of nADT, inflammation and immune-related pathways were activated, accompanied by a robust infiltration of both CD8
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