Distinct cellular mechanisms underlie chemotherapies and PD-L1 blockade combinations in triple-negative breast cancer
Yuanyuan Zhang, Hongyan Chen, Hongnan Mo, Ning Zhao, Xiaoying Sun, Baolin Liu, Ranran Gao, Binghe Xu, Zemin Zhang, Zhihua Liu, Fei Ma
Abstract
Combining immune checkpoint blockade (ICB) with chemotherapy shows promise for treating triple-negative breast cancer (TNBC), though the mechanisms remain incompletely understood. Here, we integrate published and new single-cell RNA sequencing (scRNA-seq) data to investigate the tumor immune microenvironment (TIME) in TNBC patients treated with paclitaxel (PTX), nab-paclitaxel (Nab-PTX), and their combinations with the anti-PD-L1 antibody atezolizumab (ATZ). Compared to ATZ plus PTX, ATZ plus Nab-PTX rewires TCF7 + stem-like effector memory CD8 + T cells (Tsem) and CD4 + T follicular helper (Tfh) cells. Nab-paclitaxel, unlike PTX, also reshapes the myeloid compartment, expanding mast cells and pro-inflammatory macrophages. Our analyses in human TNBC and murine models underscore the crucial role of mast cells in orchestrating anti-tumor immune responses, likely by promoting the recruitment and activation of T and B cells. In vivo experiments demonstrate that activating mast cells alongside PD-L1 blockade attenuates TNBC progression, suggesting mast cells as a promising adjunct for enhancing ICB therapy efficacy.