TREM2+ macrophages regulate suppressive tumor microenvironment in TNBC

Abstract Triple negative breast cancer (TNBC) possesses the poorest prognosis among the major breast cancer subtypes due to the limited treatment options. Nevertheless, TNBC is more immune-activated than other subtypes due to the higher mutation load, implicating that TNBC patients might benefit from immunotherapy. Previous studies have reported that the presence of tumor infiltrating lymphocytes in TNBC might create a suppressive immune microenvironment, which is associated with worse prognosis. Therefore, our work aims to compare the tumor microenvironment (TME) differences among breast cancer subtypes and discover the targetable Achilles’ heel of TNBC. We utilized public single-cell RNA-Seq (scRNA-Seq) dataset to analyze the cell composition and cell-cell communication network differences between TNBC and other subtypes. Further differential gene analysis and enrichment analysis was performed to define the transcriptomic variation. Our data showed that TREM2+ macrophages were elevated in TNBC and centrally located in the communication network. Finally, survival analysis was conducted in large cohort data to assess the involvement of TREM2+ macrophages in the progression of TNBC. Notably, the advanced TREM2+ macrophage signature was implicated with the survival outcomes of TNBC patients but not all breast cancer patients. Accordingly, this study uncovered a highly suppressive TME in TNBC, highlighted the essential role of TREM2+ macrophages in regulating the TME in TNBC, and revealed TREM2+ macrophages as a promising target for generating more favorable therapies in TNBC treatment.