Background Androgen deprivation therapy (ADT) is the cornerstone treatment for recurrent and metastatic prostate cancer. ADT has several immunomodulatory effects including T cell infiltration into the prostate and enhancing antigen processing and/or presentation.^1–3 While ADT is pivotal in prostate cancer treatment, its effectiveness with different ADT agents on T cell responses is complex and not yet fully understood.³ Our study expands upon previous research indicating that combining AR vaccination with ADT enhances AR specific CD8+T cell infiltration.² We directly compare various ADT approaches, including AR degraders and AR antagonists, to determine their synergy with AR-specific immunization. Subsequently, we identify the optimal combination for enhancing anti-tumor responses using checkpoint blockade.

Methods Prostate cancer cell lines were cultured under testosterone-replete and -deficient conditions to assess changes in AR expression post-androgen deprivation. Subsequent AR-specific T-cell recognition assays were performed after treating tumor cells with various AR-targeted agents. In vivo experiments involved combining ADT with AR-targeted vaccination and either enzalutamide or ARV110 with anti-PD-1 in murine prostate tumor models. Tumor growth, survival rates, and immune cell infiltration were monitored and evaluated.

Results AR antagonist treatment led to a significant increase in AR expression in androgen-dependent prostate tumor cells. Additionally, treatment with AR antagonists, but not AR degraders, augmented AR-specific T-cell recognition. In vivo studies demonstrated that combining ADT with AR vaccination and enzalutamide resulted in superior anti-tumor responses and prolonged survival compared to ARV110. Furthermore, Enzalutamide treatment in combination with ADT and AR vaccination increased CD4+ and CD8+T-cell infiltration within the tumor microenvironment, with a notable presence of effector memory CD8+T cells. However, when combined with anti-PD-1, there was an increase in the infiltration of regulatory T cells (Tregs).

Conclusions Our findings highlight the potential of combining ADT with AR-targeted vaccination and AR antagonists such as enzalutamide to enhance anti-tumor responses in prostate cancer. Enzalutamide, as opposed to ARV110, demonstrated superior efficacy in improving T-cell infiltration and generating memory CD8+T cell populations within the tumor microenvironment. While the addition of PD-1 blockade to this combination showed only modest benefits, it led to an increase in intratumoral regulatory CD4+T cells, suggesting a complex interplay between immune activation and regulation with combination therapies. Overall, our study provides valuable insights into optimizing therapeutic strategies for prostate cancer treatment.

References

1. Neklesa T, Snyder LB, Willard RR, et al. ARV-110: an oral androgen receptor PROTAC degrader for prostate cancer. JCO. 2019;37:259–259.

2. Muralidhar A, Gamat-Huber M, Vakkalanka S, McNeel DG. Sequence of androgen receptor-targeted vaccination with androgen deprivation therapy affects anti-prostate tumor efficacy. J Immunother Cancer. 2024;12:e008848.

3. Xu P, Yang JC, Chen B, et al. Androgen receptor blockade resistance with enzalutamide in prostate cancer results in immunosuppressive alterations in the tumor immune microenvironment. J Immunother Cancer. 2023;11:e006581.