[A multi-level study of androgen deprivation therapy on the immune microenvironment in prostate cancer].

OBJECTIVE

To systematically evaluate the impact of androgen deprivation therapy (ADT) on the immune microenvironment of prostate cancer at the levels of systemic immunity, animal model transcriptomics, and single-cell omics, and to elucidate the characteristics of ADT-mediated tumor immune remodeling.

METHODS

Twelve prostate cancer patients who received ADT at Peking University People' s Hospital were enrolled. Dynamic monitoring of serum prostate specific antigen (PSA), testosterone levels, peripheral blood immune cell proportions, and cytokine expression changes was performed. Transcriptomic data from patient-derived tumor xenograft (PDX) models before and after castration (GSE41193, 5 cases in total) were downloaded from the gene expression omnibus (GEO) database for relevant bioinformatics analyses. Single-cell RNA sequencing (scRNA-seq) was performed on 4 prostate cancer tissue samples (2 received neoadjuvant ADT, 2 untreated) to analyze tumor microenvironment cell composition and T-cell functional states.

RESULTS

ADT significantly reduced serum PSA and testosterone levels in the patients, but had no significant effect on peripheral blood immune cell proportions or most cytokines. PDX model analysis showed that differentially expressed genes after castration were enriched in neural-related and immune regulation pathways, with trending changes observed in the infiltration characteristics of various immune cells. scRNA-seq results indicated a decreased proportion of intratumoral effector CD8+ T cells after ADT treatment, with downregulated expression of cytotoxicity-related genes, such as GZMA, GZMB, GNLY, and NKG7, while regulatory T cells (Tregs) were relatively enriched. Hallmark pathway analysis revealed suppression of interferon signaling pathways.

CONCLUSION

The preliminary results of this study suggest that ADT can induce a trend of change in the tumor immune microenvironment of prostate cancer, characterized by weakened T-cell killing function and enrichment of immunosuppressive cells. This suggests that ADT may promote the formation of an immunosuppressive tumor immune microenvironment (TIME), providing a theoretical basis for ADT combined with immune-modulating therapeutic strategies.