Integrated transcriptome and single-cell sequencing reveals M2-like tumor-associated macrophages-related prognostic signatures in breast cancer

Abstract Background: M2-like tumor-associated macrophages (M2-like TAMs) have crucial functions in the tumor microenvironment (TME) and cancer development. This study explored M2-like TAMs-related prognostic signatures in breast cancer (BRCA) by combining transcriptome and scRNA-seq. Methods: All datasets (TCGA-BRCA, GSE20685, GSE176078) were downloaded from UCSC xena and GEO database. AUCell score of immune-related genes (IRGs) was calculated using R package. M2-like TAMs-related genes were screened by WGCNA. Signature genes predictive of BRCA prognosis were identified by univariate Cox and LASSOregression analyses. Then, RiskScore model was constructed and validated in external dataset. Nomogram was established by integrating RiskScore and clinical characteristics. Correlation analysis between RiskScore and TME or chemotherapeutic drugs was conducted. Results: Macrophage exhibited the highest IRGs AUCell score in single-cell transcriptomic atlas of BRCA. Macrophage was split into C1 and C2 subtypes, and Macrophage C1 highly expressed the marker genes of M2 macrophages. Then, 903 M2-like TAMs-related genes were acquired. ARHGAP26, RILP, KLRB1, CSTA, KLHDC7B, PSMB8, KYNU, RNASE1, LONRF3, and TRPM2were screened as prognostic signatures to establish RiskScore model, exhibiting good robustness. Nomogram was constructed by combining stage, Age, and RiskScore, with good predictive performance. Besides, most immune cells showed a negative correlation with RiskScore. Eight drugs were notably correlated with RiskScore, and the high-risk group had higher half maximal inhibitory concentration (IC50) of Ribociclib_1632, conversely indicating that the BRCA patients with low RiskScore were more sensitive to Ribociclib_1632. Conclusion: We identified 10 M2-like TAMs-related prognostic signatures, providing potential therapeutic targetsfor BRCA.