Distinct Cellular Mechanisms Underlie Chemotherapies and Their Combinations with PD-L1 Checkpoint Inhibitor in Triple-Negative Breast Cancer [TNBC]

The combination of immune checkpoint blockade (ICB) and chemotherapy holds promise for treating triple-negative breast cancer (TNBC), yet the underlying mechanisms remain incompletely understood. Here, we integrated previously published and newly generated single-cell RNA sequencing (scRNA-seq) data to investigate the tumor immune microenvironment (TIME) in advanced TNBC patients receiving various therapies, including paclitaxel, nab-paclitaxel, and their combinations with an anti-PD-L1 antibody atezolizumab. Notably, compared to atezolizumab plus paclitaxel, atezolizumab plus nab-paclitaxel primarily rewired TCF7+ stem-like effector memory CD8 T cells (Tsem) and CD4 follicular helper T (Tfh) cells. Nab-paclitaxel, but not paclitaxel, predominantly modulated the myeloid compartment, expanding mast cells and pro-inflammatory macrophage subsets. Our analyses in human TNBC and murine models highlighted the crucial role of mast cells in orchestrating anti-tumor immune responses, likely by recruiting and activating T cells and B cells. In vivo experiments demonstrated that activating mast cells alongside PD-L1 blockade significantly attenuated tumor progression, suggesting mast cells as a promising adjunct for enhancing ICB therapy efficacy.