Basal-like breast cancer (BLBC) is a type of high-grade invasive breast cancer with high risk of recurrence, metastases, and poor survival. Immune activation in BLBC is a key factor that influences both cancer progression and therapeutic response, although its molecular mechanisms are not well clarified. In this study, we examined five cancer immunity-related pathways (IFNα, IFNγ, STAT3, TGFβ and TNFα) in four large independent breast cancer cohorts (n = 6,381) and their associations with the prognosis of breast cancer subtypes. Activities of the 5 pathways were calculated based on corresponding pathway signatures and associations between pathways and clinical outcomes were examined by survival analysis. Among the five PAM50-based subtypes, BLBC had the highest IFNα, IFNγ, TNFα pathway activities, and the lowest TGFβ activity. The IFNα, IFNγ, TNFα pathway activities were negatively correlated with BLBC recurrence. In contrast, positive association and no association with BLBC recurrence were observed for TGFβ and STAT3 pathways, respectively. TNFα/TGFβ pathway combination improved the prediction of recurrence and chemotherapy response of BLBCs. Immune cell subset analysis in BLBC showed that M0, M1 and M2 macrophage levels were associated with either TNFα or TGFβ pathways, whereas the level of activated memory CD4 T cells were associated with both pathways. Moreover, this T cell subset was most abundant in BLBCs with low TGFβ and high TNFα pathway activities. These results suggested that cooperation of TNFα and TGFβ signaling may be involved in the regulation of memory T cells and anti-cancer immunity in BLBCs. Our data also demonstrate that TNFα/TGFβ pathway combination may represent a better biomarker for BLBC prognosis and clinical management.

中文翻译：

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低TGFβ、高TNFα通路活性的基底样乳腺癌富含活化的记忆CD4+T细胞，预后良好

基底样乳腺癌（BLBC）是一种高度浸润性乳腺癌，具有高复发、转移风险和低生存率。BLBC 中的免疫激活是影响癌症进展和治疗反应的关键因素，尽管其分子机制尚未得到很好的阐明。在这项研究中，我们检查了四个大型独立乳腺癌队列中的五个癌症免疫相关通路（IFNα、IFNγ、STAT3、TGFβ 和 TNFα）（n= 6,381) 及其与乳腺癌亚型预后的关系。5 种途径的活性根据相应的途径特征进行计算，并通过生存分析检查途径与临床结果之间的关联。在五种基于 PAM50 的亚型中，BLBC 具有最高的 IFNα、IFNγ、TNFα 通路活性和最低的 TGFβ 活性。IFNα、IFNγ、TNFα通路活性与BLBC复发呈负相关。相反，分别观察到 TGFβ 和 STAT3 通路与 BLBC 复发呈正相关和无相关。TNFα/TGFβ通路组合提高了对BLBCs复发和化疗反应的预测。BLBC 中的免疫细胞亚群分析表明，M0、M1 和 M2 巨噬细胞水平与 TNFα 或 TGFβ 通路相关，而激活的记忆 CD4 T 细胞水平与这两种途径相关。此外，该 T 细胞亚群在具有低 TGFβ 和高 TNFα 通路活性的 BLBC 中最为丰富。这些结果表明，TNFα 和 TGFβ 信号通路的协同作用可能参与了 BLBCs 中记忆 T 细胞和抗癌免疫的调节。我们的数据还表明，TNFα/TGFβ 通路组合可能代表 BLBC 预后和临床管理的更好生物标志物。