Construction and application of a humanized mouse model for prostate cancer in immunotherapy

Prostate cancer (PCa) exhibits low sensitivity to immune checkpoint inhibitors due to insufficient T cell infiltration and the dominance of immunosuppressive cells in the tumor immune microenvironment (TIME). Immunotherapy-based combination therapy proves to be an effective strategy in overcoming immune resistance. However, the development and optimization of such therapies necessitate an accurate preclinical model capable of replicating the complex TIME of PCa. To address this need, we developed a humanized mouse model that closely mimics the TIME of PCa patients. This model was created by transplanting human peripheral blood mononuclear cells (PBMCs) into severe combined immunodeficient mice. We systematically investigated factors influencing immune reconstitution, including donor variability, cell dosage, and recipient characteristics. Furthermore, the model was employed to establish a human PCa xenograft, which enabled us to assess the therapeutic efficacy and explore the underlying mechanisms of the combination therapy involving docetaxel and pembrolizumab. The results revealed that both the donor origin and the quantity of transplanted PBMCs had a significant impact on immune reconstitution. In our preclinical evaluations, the combination therapy of docetaxel with immunotherapy showed superior efficacy in both cell line-derived and patient-derived xenograft models when compared to monotherapy approaches. This enhanced efficacy is attributed to the increased infiltration of CD8⁺ T cells within the TIME. Our study successfully establishes a reliable humanized mouse model for PCa. The promising outcomes of the combination therapy observed in this model could potentially lay the groundwork for innovative clinical applications designed to overcome immune resistance in PCa.