Identification of hypoxia-immune-related signatures for predicting immune efficacy in triple-negative breast cancer

Abstract

OBJECTIVES: The therapeutic effect against triple-negative breast cancer (TNBC) varies among individuals. Finding signatures to predict immune efficacy is particularly urgent. Considering the connection between the microenvironment and hypoxia, hypoxia-related signatures could be more effective. Therefore, in this study, we aimed sought to construct a hypoxia-immune-related prediction model for breast cancer and identify therapeutic targets. METHODS: Immune and hypoxia status in the TNBC microenvironment were investigated using single-sample Gene Set Enrichment Analysis (ssGSEA) and Uniform Manifold Approximation and Projection (UMAP). The least absolute shrinkage and selection operator (LASSO) and multivariate Cox regression analysis were employed to build a prognostic model based on hypoxia-immunerelated differentially expressed genes. The Cancer Genome Atlas (TCGA) cohort, real-time quantitative polymerase chain reaction (qRT-PCR), and immunofluorescence staining were utilized to analyze the expression differences. Tumor immune dysfunction and exclusion indexes were used to indicate the effect of immunotherapy. RESULTS: We identified 11 signatures related to hypoxia and immunity. Among these genes, C-X-C motif chemokine ligand (CXCL) 9, 10, and 11 were up-regulated in TNBC tissues compared to normal tissues. Furthermore, CXCL9, 10, 11, and 13 were found to enhance the effect of immunotherapy. CONCLUSIONS: These findings suggest the value of the hypoxia-immune-related prognostic model for estimating the risk in patients with TNBC, and CXCL9, 10, 11, and 13 are potential targets to overcome immune resistance in TNBC.