Analysis of Tumor Microenvironment Heterogeneity among Breast Cancer Subtypes to Identify Subtype-Specific Signatures

Breast cancer is one of the most frequent malignancies in women worldwide. According to 50-gene signature, Prediction Analysis of Microarray 50 (PAM50), breast cancer can be categorized into five molecular subtypes, and these subtypes are highly heterogeneous in different molecular characteristics. However, the landscape of their tumor microenvironment (TME) heterogeneity has not been fully researched. Using the multi-omics dataset of breast cancer from the METABRIC cohort (n = 1699), we conducted extensive analyses of TME-related features to investigate TME heterogeneity in each breast cancer subtype. We then developed a cell-based subtype set enrichment analysis to identify the subtype-specific TME cells, and further evaluate their prognostic effects. Our results illustrate that different breast cancer subtypes exhibit different TME patterns. Basal-like and HER2-enriched subtypes are associated with high immune scores, expression of most immune regulatory targets, and immune cell infiltration, suggesting that these subtypes could be defined as "immune hot" tumors and suitable for immune checkpoint blockade (ICB) therapy. In contrast, Luminal A and Luminal B subtypes are associated with low immune scores and immune cell infiltration, suggesting that these subtypes could be defined as "immune cold" tumors. Additionally, the Normal-like subtype has relatively high levels of both immune and stromal features, which indicates that the Normal-like subtype may be suitable for more diverse treatment strategies. Our study reveals the breast cancer tumor microenvironment heterogeneity across subtypes. The comprehensive analysis of breast cancer TME-related characteristics may help us to adopt a tailored treatment strategy for different subtypes of patients.