Abstract:

Triple-negative breast cancer （TNBC） lacks ER/PR/HER2 targets， exhibits high aggressiveness， and is associated with poor prognosis. Tumor?infiltrating B-cells （TIL-B） have emerged as key modulators of both antitumor immunity and immune escape， yet their specific roles in TNBC and impact on immune checkpoint inhibitor （ICI） efficacy remain incompletely understood. We analyzed two publicly available single-cell RNA-seq datasets of TNBC from GEO to identify and annotate TIL-B subpopulations. Samples were stratified into “activated” and “suppressed” B-cell groups via unsupervised clustering. Immune infiltration， cell-cell communication networks， and survival differences between these groups were assessed in the TCGA-TNBC cohort and validated across independent GEO datasets. LASSO and Cox regression were employed to screen key prognostic genes and to build a four-gene risk model. The activated B-cell group exhibited significantly enhanced intercellular immune signaling， higher infiltration of CD8⁺ T cells and NK cells， and improved overall survival （P=0.016）. The prognostic model comprising JCHAIN， F11R， IGHG3， and CD24 achieved AUCs of 0.82， 0.72， and 0.81 for 1-， 3-， and 5-year survival predictions in the TCGA cohort， respectively， and was robustly validated in independent datasets. By prospectively profiling B-cell activation states in TNBC， we reveal their potential roles in antitumor immunity and ICI response. The four-gene prognostic risk model offers a robust tool for individualized immunotherapeutic decision?making and B-cell-targeted interventions.

Key words: triple-negative breast cancer, B-cell activation, tumor immune microenvironment, single-cell RNA sequencing, four-gene prognostic model, cell-cell communication

摘要：

三阴性乳腺癌（triple-negative breast cancer，TNBC）缺乏ER/PR/HER2靶点，表现出高度侵袭性，并与不良预后相关。肿瘤浸润B细胞（tumor-infiltrating B-cells，TIL-B）已被认为是抗肿瘤免疫与免疫逃逸的关键调控者之一，但其在TNBC中的具体作用及对免疫检查点抑制剂（immune checkpoint inhibitors，ICI）疗效的影响尚未完全阐明。对GEO数据库中2个TNBC单细胞RNA测序数据进行分析，用于识别并注释TIL-B亚群。通过无监督聚类将样本分为“激活型”和“抑制型”B 细胞组。在TCGA-TNBC队列中比较2组B细胞的免疫浸润、细胞间通讯网络及生存差异，并在独立GEO队列中进行验证。采用LASSO与Cox回归筛选关键预后基因，并构建四基因风险模型。激活型B细胞组表现出显著增强的细胞间免疫信号、更高水平的CD8⁺ T细胞与NK细胞浸润，以及改善的总体生存率（P=0.016）。由JCHAIN、F11R、IGHG3与CD24构成的预后模型在TCGA队列中分别实现了1、3和5年生存预测的AUCs为0.82、0.72和0.81，并在独立数据集中得到了稳健验证。通过对TNBC中B细胞激活状态的前瞻性描绘，揭示了其在抗肿瘤免疫及ICI应答中的潜在作用。四基因预后风险模型为个体化免疫治疗决策及B细胞靶向干预提供了有力工具。

关键词: 三阴性乳腺癌, B细胞激活, 肿瘤免疫微环境, 单细胞RNA测序, 四基因预后模型, 细胞-细胞通讯