Temporal dynamics of the immune response to neoadjuvant androgen deprivation therapy suggest a window of opportunity for checkpoint inhibitor therapy in prostate cancer

Abstract

Abstract Background 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 microenvironment (TiME) following neoadjuvant ADT (nADT). Methods Radical prostatectomy specimens from 43 nADT-treated patients were stratified into three duration groups and compared with each other and with 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 cytotoxic T lymphocytes (CTLs) and T-helper cells after 3–5 months of nADT. However, after 6 months nADT, M2-like tumor-associated macrophages (TAMs) and regulatory T cells were strikingly increased while CTLs decreased. Spatially, CTLs and T-helper cells clustered near tumor cells at 3–5 months nADT, but were replaced by M2-TAMs in tumors receiving ≥6 months of nADT. Conclusions 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.