Integrated analysis of single-cell and bulk RNA sequencing identifies a signature based on macrophage marker genes involved in prostate cancer prognosis and treatment responsiveness

Abstract

In the tumor microenvironment, tumor-associated macrophages (TAMs) interact with cancer cells and contribute to the progression of solid tumors. Nonetheless, the clinical significance of TAM-related biomarkers in prostate cancer (PCa) is largely unexplored. The present study aimed to construct a macrophage-related signature (MRS) for predicting PCa patient prognosis based on macrophage marker genes. Six cohorts comprising 1056 PCa patients with RNA-Seq and follow-up data were enrolled. Based on macrophage marker genes identified by single-cell RNA-sequencing (scRNA-seq) analysis, univariate analysis, least absolute shrinkage and selection operator (Lasso)-Cox regression, and machine learning procedures were performed to derive a consensus MRS. Receiver operating characteristic curve (ROC), concordance index, and decision curve analyses were used to confirm the predictive capacity of the MRS. The predictive performance of the MRS for recurrence-free survival (RFS) was stable and robust, and the MRS outperformed traditional clinical variables. Furthermore, high-MRS-score patients presented abundant macrophage infiltration and high-expression levels of immune checkpoints (CTLA4, HAVCR2, and CD86). The frequency of mutations was relatively high in the high-MRS-score subgroup. However, the low-MRS-score patients had a better response to immune checkpoint blockade (ICB) and leuprolide-based adjuvant chemotherapy. Notably, abnormal ATF3 expression may be associated with docetaxel and cabazitaxel resistance in PCa cells, T stage, and the Gleason score. In this study, a novel MRS was first developed and validated to accurately predict patient survival outcomes, evaluate immune characteristics, infer therapeutic benefits, and provide an auxiliary tool for personalized therapy.