Basal-like breast cancer with low TGFβ and high TNFα pathway activity is rich in activated memory CD4 T cells and has a good prognosis

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 (IFN alpha, IFN gamma, STAT3, TGF beta and TNF alpha) 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 IFN alpha, IFN gamma, TNF alpha pathway activities, and the lowest TGF beta activity. The IFN alpha, IFN gamma, TNF alpha pathway activities were negatively correlated with BLBC recurrence. In contrast, positive association and no association with BLBC recurrence were observed for TGF beta and STAT3 pathways, respectively. TNF alpha/TGF beta 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 TNF alpha or TGF beta 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 TGF beta and high TNF alpha pathway activities. These results suggested that cooperation of TNF alpha and TGF beta signaling may be involved in the regulation of memory T cells and anti-cancer immunity in BLBCs. Our data also demonstrate that TNF alpha/TGF beta pathway combination may represent a better biomarker for BLBC prognosis and clinical management.

Automated summary

Basal-like breast cancer (BLBC) is a high-grade invasive breast cancer subtype with high risk of recurrence and poor survival. Immune activation, specifically involving IFN-alpha, IFN-gamma, and TNF-alpha pathways, negatively correlates with BLBC recurrence, while TGF-beta and STAT3 pathways show positive or no association. Combining TNF-alpha/TGF-beta pathways improves prediction of recurrence and chemotherapy response in BLBCs.