Immune Cell Infiltration-Based Characterization of Triple-Negative Breast Cancer Predicts Prognosis and Chemotherapy Response Markers

Abstract

Breast cancer represents the number one cause of cancer-associated mortality globally. The most aggressive molecular subtype is triple negative breast cancer (TNBC), of which limited therapeutic options are available. It is well known that breast cancer prognosis and tumor sensitivity toward immunotherapy are dictated by the tumor microenvironment. Breast cancer gene expression profiles were extracted from the METABRIC dataset and two TNBC clusters displaying unique immune features were identified. Activated immune cells formed a large proportion of cells in the high infiltration cluster, which correlated to a good prognosis. Differentially expressed genes (DEGs) extracted between two heterogeneous subtypes were used to further explore the underlying immune mechanism and to identify prognostic biomarkers. Functional enrichment analysis revealed that the DEGs were predominately related to some processes involved in activation and regulation of innate immune signaling. Using network analysis, we identified two modules in which genes were selected for further prognostic investigation. Validation by independent datasets revealed that CXCL9 and CXCL13 were good prognostic biomarkers for TNBC. We also performed comparisons between the above two genes and immune markers (CYT, APM, TILs, and TIS), as well as cell checkpoint marker expressions, and found a statistically significant correlation between them in both METABRIC and TCGA datasets. The potential of CXCL9 and CXCL13 to predict chemotherapy sensitivity was also evaluated. We found that the CXCL9 and CXCL13 were good predictors for chemotherapy and their expressions were higher in chemotherapy-responsive patients in contrast to those who were not responsive. In brief, immune infiltrate characterization on TNBC revealed heterogeneous subtypes with unique immune features allowed for the identification of informative and reliable characteristics representative of the local immune tumor microenvironment and were potential candidates to guide the management of TNBC patients.