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.

A comprehensive bioinformatics analysis to identify potential prognostic biomarkers among CC and CXC chemokines in breast cancer

“…Also, we found higher CXCL9 levels in patients with higher SBR grades. More importantly, a high expression level of CXCL9 was significantly linked to lymphocytes infiltration and better response to chemotherapy in BC patients 64 – 67 .…”

Spatial Profiling Identifies Prognostic Features of Response to Adjuvant Therapy in Triple Negative Breast Cancer (TNBC)

“…In addition to our study, other deep profiling methods to evaluate TIL subtypes and cellular markers associated with therapy response in TNBC have included multiplex imaging ( 42 ), bioinformatic deconvolution of bulk public mRNA data ( 43 , 44 ), and RNAseq of tumours stratified by CD8+ TIL abundance ( 45 , 46 ). Our data here provides an additional layer of insight into TNBC tumour composition.…”

Potential Role of CXCL13/CXCR5 Signaling in Immune Checkpoint Inhibitor Treatment in Cancer

“…CD8 + and CD4 + T cells, cancer-associated fibroblasts, cancer cells, and dendritic cells are able to secrete CXCL13, and CD8 + and CD4 + T cells, B cells, and cancer cells express CXCR5 ( Figure 2 ). Increasing research has reported the detection of CXCL13 in the tumor microenvironment of many different types of cancer [ 103 , 104 , 105 , 106 , 107 , 108 , 109 ]. When the cancer microenvironment is enriched in CXCL13, the recruitment of CXCR5-expressing leukocytes to the tumor microenvironment increases.…”