Single-cell Atlas Reveals a Distinct Immune Profile Fostered by T cell-B cell Crosstalk in Triple Negative Breast Cancer

Background: Characterizing the unique immune microenvironment of each tumor is of great importance for better predicting prognosis and guiding cancer immunotherapy. However, the unique features of the immune microenvironment of triple negative breast cancer (TNBC) compared with other subtypes of breast cancer remain elusive. Therefore, we aimed to depict and compare the immune landscape among TNBC, human epidermal growth factor receptor 2-positive (HER2 ) breast cancer, and luminal-like breast cancer.

Methods: Single-cell RNA sequencing (scRNA-seq) was performed on CD45 immune cells isolated from human normal breast tissues and primary breast tumors of various subtypes. By analyzing the scRNA-seq data, immune cell clusters were identified and their proportions as well as transcriptome features were compared among TNBC, human HER2 breast cancer, and luminal-like breast cancer. Pseudotime and cell-cell communication analyses were also conducted to characterize the immune microenvironment.

Results: ScRNA-seq data of 117,958 immune cells were obtained and 31 immune clusters were identified. A unique immunosuppressive microenvironment in TNBC was decoded as compared to that in HER2 or luminal-like breast cancer, which was characterized by higher proportions of regulatory T cells (Tregs) and exhausted CD8 T cells and accompanied by more abundant plasma cells. Tregs and exhausted CD8 T cells in TNBC exhibited increased immunosuppression signature and dysfunctional scores. Pseudotime analyses showed that B cells tended to differentiate to plasma cells in TNBC. Cell-cell communication analyses indicated that these unique features are fostered by the diversified T cell-B cell crosstalk in TNBC. Based on the T cell-B cell crosstalk, a prognostic signature was established that could effectively predict the prognosis status for patients with TNBC. Additionally, it was found that TNBC had a higher proportion of cytotoxic natural killer (NK) cells, whereas HER2 or luminal-like breast cancer lost this feature, suggesting that HER2 or luminal-like breast cancer, but not TNBC, may benefit from NK-based immunotherapy.

Conclusions: This study identified a distinct immune feature fostered by T cell-B cell crosstalk in TNBC, which provides better prognostic information and effective therapeutic targets for breast cancer.