Purpose: To develop a neutrophil-related gene signature that can be used to predict survival outcomes and direct individualized therapy of triple-negative breast cancer (TNBC) patients.

Study Design: iTRAQ-based proteomics analysis of breast cancer tissues and bioinformatics analysis of TCGA-BRCA dataset were performed to evaluate the pathways enriched in TNBC. Immunohistochemistry was used to determine neutrophil infiltration in TNBC vs. non-TNBC tissues. Univariate and multivariate Cox analyses were performed on TCGA-TNBC dataset to derive a neutrophil-related gene signature (NRGS) and develop a risk score to stratify TNBC patients into high- and low-risk groups. A nomogram model was generated by incorporating the NRGS with clinicopathological parameters to predict survival outcomes of TNBC patients. The NRGS was analyzed for tumor immune microenvironment and response to immune checkpoint inhibitors as well as sensitivity to therapeutic drugs. A Gene Expression Omnibus (GEO) dataset (GSE58812) was used for independent validation.

Results: iTRAQ-based proteomics profiling of breast cancer tissue samples and bioinformatics analysis of TCGA-BRCA dataset revealed neutrophil-related pathways as the top enriched pathways in TNBC. A higher level of neutrophil infiltration was demonstrated by immunohistochemistry on TNBC compared with non-TNBC tissues. A 9-gene NRGS was identified and used to derive a risk score to stratify TNBC patients into high- and low-risk groups. A nomogram model with superior predicting power was generated via incorporating the NRGS with clinical tumor stage and pathological nodal status. Furthermore, high-risk TNBC patients were associated with immune suppression, expressed lower levels of immune checkpoints, and exhibited lower sensitivity to CTLA4 and PD1/PDL1 blockers. Through screening classic and non-classic therapeutic agents, we found that high-risk TNBC patients had enhanced sensitivity to nuclear receptor-targeting agents such as SR8278 and VAF-347.

Conclusions: A neutrophil-related gene signature and its derived nomogram model could predict immune status and sensitivity to nuclear receptor-targeting agents in TNBC patients.

Xiyun Deng is a professor of Pathophysiology, chair of Department of Basic Medical Sciences, and director of Key Laboratory of Translational Cancer Stem Cell Research at Hunan Normal University. His research focuses on experimental therapeutics targeting cancer stem cells and the tumor microenvironment. In recent years, triple-negative breast cancer (TNBC) has been a focus of intense investigations for his lab. With continued funding support by grants from the National Science Foundation of China and other sources, his team has found that: 1) post-translational modifications of non-histone proteins play a crucial role in EMT/metastasis, metabolic reprogramming and drug-induced cellular stress responses in cancer stem cells; and 2) dysregulated immune microenvironment provides novel therapeutic targets for cancer. Dr. Deng has published over 100 articles/reviews in high-impact professional journals such as Blood, Clinical Cancer Research, Cancer Treatment Reviews, ACS Applied Materials & Interfaces, International Journal of Cancer, Biomaterials Science, etc. He is currently guest-editing a Research Topic for Frontiers in Oncology regarding heterogeneity, tumor microenvironment and targeted therapy in triple-negative breast cancer. As a principal editor, he has compiled a book titled “Triple-Negative Breast Cancer”, which was published by World Scientific Publishing (Singapore).