J Cancer 2020; 11(6):1568-1583. doi:10.7150/jca.37637

Research Paper

Tumour-Infiltrating Immune Cell-Based Subtyping and Signature Gene Analysis in Breast Cancer Based on Gene Expression Profiles

Jingxin Jiang1,3*, Weiwei Pan1,3*, Yazhang Xu1,3*, Chao Ni1,3, Dan Xue2,3, Zhigang Chen1,3, Wuzhen Chen1,3✉, Jian Huang1,3✉

1. Department of Breast Surgery (Surgical Oncology), Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
2. Department of Plastic Surgery, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
3. Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, Hangzhou, China
*. These authors contributed equally to this work.

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Citation:
Jiang J, Pan W, Xu Y, Ni C, Xue D, Chen Z, Chen W, Huang J. Tumour-Infiltrating Immune Cell-Based Subtyping and Signature Gene Analysis in Breast Cancer Based on Gene Expression Profiles. J Cancer 2020; 11(6):1568-1583. doi:10.7150/jca.37637. Available from https://www.jcancer.org/v11p1568.htm

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Abstract

Tumour-infiltrating immune cells have been indicated to play an important role in prognosis prediction and therapy sensitivity for breast cancer. In recent years, estimating the abundance of immune cells based on tumour transcriptome data has provided a novel way to analyse the clinical significance of various immune cell subsets. This study integrated breast cancer tissue transcriptome datasets from the Gene Expression Omnibus (GEO), the Cancer Genome Atlas-Breast Cancer (TCGA-BRCA) and the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) cohorts. A novel breast cancer immunotyping and a new prognostic model based on tumour-infiltrating immune cell subsets have been established, aiming to provide new clues regarding prognostic prediction and precision therapy for breast cancer. The key differentially expressed gene between different breast cancer immunotypes has also been identified. We performed unsupervised clustering analysis and construct a novel immunotyping which could classify breast cancer cases into immunotype A (B_cellhigh NKhigh CD8+_Thigh CD4+_memory_T_activatedhigh γδTlow Mast_cell_activatedlow Neutrophillow) and immunotype B (B_celllow NKlow CD8+_Tlow CD4+_memory_T_activatedlow γδThigh Mast_cell_activatedhigh Neutrophilhigh) in luminal B, HER2-enriched and basal-like subtypes. The 5-year (85.7% vs. 73.4%) and 10-year OS (75.60% vs. 61.73%) of immunotype A population were significantly higher than those of immunotype B. A novel tumour-infiltrating immune cell-based prognostic model had also been established and the result immunorisk score (IRS) could serve as a new prognostic factor for luminal B, HER2-enriched and basal-like breast cancer. The higher IRS was, the worse prognosis was. We further screened the differentially expressed genes between immunotype A and B and identified a novel breast cancer immune-related gene, prostaglandin D2 synthase (PTGDS) and higher PTGDS mRNA expression level was positively correlated with earlier TNM stage. Immune-related signaling pathways analysis and immune cell subsets correlation analysis revealed that PTGDS expression was related with abundance of B cells, CD4+ T cells and CD8+ T cells, which was finally validated by immunohistochemical and immunofluorescence staining. We established a novel immunotyping and a tumour-infiltrating immune cell-based prognostic prediction model in luminal B, HER2-enriched and basal-like breast cancer by analyzing the prognostic significance of multiple immune cell subsets. A novel breast cancer immune signature gene PTDGS was discovered, which might serve as a protective prognostic factor and play an important role in breast cancer development and lymphocyte-related immune response.

Keywords: breast cancer, tumour-infiltrating immune cell, immunotyping, prognostic prediction model, prostaglandin D2 synthase (PTGDS)