Androgen Receptor (AR) Expression is Associated with an Immune-Cold Phenotype and Reduced Response to Immune Checkpoint Inhibitors in ER-Positive/HER2-Negative Breast Cancer

Background Immune checkpoint inhibitors (ICIs) have limited efficacy in estrogen receptor-positive/human epidermal growth factor receptor 2-negative (ER+/HER2-) breast cancer, and the mechanisms underlying immune resistance remain unclear. The androgen receptor gene ( AR ), expressed in a substantial proportion of ER-positive tumors, has been implicated in tumor biology; however, its role in the tumor immune microenvironment and immunotherapy response is not well understood. Methods We investigated the association between AR expression, transcriptome-derived immune cell-associated signatures, and response to ICIs in 4046 patients with breast cancer across five cohorts with bulk transcriptomic data and two cohorts with single-cell transcriptomic data. Results High AR expression was consistently associated with reduced transcriptome-derived tumor-infiltrating leukocyte scores across multiple ER+/HER2- cohorts. Specifically, signatures associated with cluster of differentiation (CD)-8+ T-cell subsets, dendritic cells, and M1 macrophages were significantly reduced in AR -high tumors, indicating a transcriptionally immune-suppressed tumor microenvironment. In the I-SPY2 cohort, AR -high tumors demonstrated significantly lower pathological complete response rates after neoadjuvant ICI therapy. Furthermore, AR expression showed a predictive performance for ICI response that was superior to that with programmed cell death protein-1 and programmed cell death ligand-1 (area under the curve 0.82 vs. 0.73 and 0.60, respectively). Interestingly, single-cell analysis revealed that AR expression across multiple cell types, including epithelial, endothelial, and myeloid, was associated with reduced ICI responsiveness. Additionally, AR inhibition using enzalutamide was associated with increased signatures associated with CD8+ T cells, dendritic cells, and M1 macrophages. Conclusions These findings suggest that AR expression is associated with an immunosuppressive tumor microenvironment and reduced response to ICIs in ER+/HER2- breast cancer.