Bluewater Biotech LLC, New Providence, NJ, USA.
Division of Cancer Research and Training, Department of Internal Medicine, Charles Drew University of Medicine and Science, David Geffen UCLA School of Medicine and UCLA Jonsson Comprehensive Cancer Center, Los Angeles, CA 90095, USA.
Int J Biol Sci. 2021 Jan 30;17(3):670-682. doi: 10.7150/ijbs.56128. eCollection 2021.
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 ( = 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.
基底样乳腺癌（BLBC）是一种高风险的浸润性乳腺癌，具有较高的复发、转移和不良生存风险。BLBC 中的免疫激活是影响癌症进展和治疗反应的关键因素，尽管其分子机制尚不清楚。在这项研究中，我们在四个大型独立乳腺癌队列（n=6381）中检查了五个癌症免疫相关途径（IFNα、IFNγ、STAT3、TGFβ 和 TNFα）及其与乳腺癌亚型预后的关系。根据相应的途径特征计算了 5 个途径的活性，并通过生存分析检查了途径与临床结局之间的关联。在基于 PAM50 的 5 个亚型中，BLBC 具有最高的 IFNα、IFNγ、TNFα 途径活性和最低的 TGFβ 活性。IFNα、IFNγ、TNFα 途径活性与 BLBC 复发呈负相关。相反，TGFβ 和 STAT3 途径与 BLBC 复发呈正相关和无相关性。TNFα/TGFβ 途径组合改善了 BLBC 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 途径相关，而激活的记忆 CD4 T 细胞水平与两个途径均相关。此外，该 T 细胞亚群在 TGFβ 水平低和 TNFα 途径活性高的 BLBC 中最为丰富。这些结果表明，TNFα 和 TGFβ 信号的协同作用可能参与了 BLBC 中记忆 T 细胞和抗肿瘤免疫的调节。我们的数据还表明，TNFα/TGFβ 途径组合可能代表 BLBC 预后和临床管理的更好生物标志物。
