Introduction:

Immune checkpoint inhibitors (ICIs) demonstrate limited efficacy in prostate cancer (PCa), particularly in patients undergoing androgen deprivation therapy (ADT). ADT has been shown to upregulate PDL-1 expression, contributing to immunotherapy resistance. Recent evidence suggests that components of the tumor immune microenvironment, including androgen-regulated pathways, may shape PDL-1 expression and influence ICI response. Protein kinase D1 (PrKD1), often downregulated in advanced PCa, has emerged as a potential modulator of immune evasion. This study evaluates PrKD1 as a therapeutic target to enhance ICI responsiveness.

Methods:

In vitro assays were performed in prostate cancer cell lines to evaluate PDL-1 expression following androgen deprivation, androgen supplementation, and PrKD1 inhibition using Compound-10 (C10), a selective PrKD1 inhibitor. Western blotting, co-immunoprecipitation, viability assays, and confocal microscopy were used to assess protein expression, molecular interactions, and subcellular localization of PKD1 and androgen receptor (AR). In vivo efficacy and tolerability of C10 were evaluated using a patient-derived xenograft (PDX) mouse model. Additionally, RNA sequencing data from The Cancer Genome Atlas (TCGA) were analyzed to compare PDL-1 expression between localized and metastatic PCa.

Results:

PDL-1 expression was significantly elevated in castration-resistant prostate cancer (CRPC) compared to non-metastatic (M0) disease (Figure 1). Androgen supplementation decreased PDL-1 levels, whereas ADT increased them. PrKD1 inhibition via C10 reduced PDL-1 expression in a dose-dependent manner and decreased cell viability (Figure 2). In vivo, C10 was well-tolerated and reduced PrKD1 kinase activity.

Conclusion:

PrKD1 may play a critical role in androgen-mediated immune evasion in advanced prostate cancer. Pharmacologic inhibition of PrKD1 using Compound-10 reduced PDL-1 expression and may enhance tumor sensitivity to immune checkpoint inhibitors. These findings highlight a novel therapeutic strategy to improve immunotherapy efficacy and support further investigation of PrKD1-targeted approaches, including combinations with ICIs or bipolar androgen therapy.

Funding: N/A