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

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_cell high NK high CD8 + _T high CD4 + _memory_T_activated high γδT low Mast_cell_activated low Neutrophil low ) and immunotype B (B_cell low NK low CD8 + _T low CD4 + _memory_T_activated low γδT high Mast_cell_activated high Neutrophil high ) 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.

M1 Polarization Markers Are Upregulated in Basal-Like Breast Cancer Molecular Subtype and Associated With Favorable Patient Outcome

“…Moreover, our findings go with the previous report that showed a significant association between poor classical clinicopathological parameters, including ER, PR negativity, LN involvement, poorly differentiated tumors, and the absolute Immunoscore, which reflects the total tumor-infiltrating immune cells (32). The same report also showed tumor-infiltrating lymphocytes (TILs) to be higher in the more aggressive HER-2 as well as basal-like breast cancer types compared to the less aggressive luminal A & B subtypes (32).…”

“…Indeed, our results provide evidence that the enrichment of tissues from IM subtype of TNBC patients with immune cell signaling and pathways observed by Lehmann et al, 2011 was not only due to epithelial tumor cells but also due to the difference in the tumor microenvironment including the immune cells as well as the stromal components surrounding the tumor ( 19 ). Moreover, our findings go with the previous report that showed a significant association between poor classical clinicopathological parameters, including ER, PR negativity, LN involvement, poorly differentiated tumors, and the absolute Immunoscore, which reflects the total tumor-infiltrating immune cells ( 32 ). The same report also showed tumor-infiltrating lymphocytes (TILs) to be higher in the more aggressive HER-2 as well as basal-like breast cancer types compared to the less aggressive luminal A & B subtypes ( 32 ).…”

The Immunology of Hormone Receptor Positive Breast Cancer

“…While low expression of MHC-I may limit CD8 T cell recognition and response to HR+ breast tumors, the lack of MHC-I molecules should in turn promote NK cell activation, representing an alternate immunotherapeutic target (99)(100)(101). In general, NK cells account for a small portion of infiltrating lymphocytes in breast tumors (102,103). Interestingly, analyses of TCGA and METABRIC samples revealed HR+ tumors have lower NK cell gene expression compared to TNBC tumors and immune-rich HR+ tumors have a lower proportions of NK cells compared to immune-rich TNBC tumors (104,105).…”

A Risk Scoring System Based on Tumor Microenvironment Cells to Predict Prognosis and Immune Activity in Triple-Negative Breast Cancer

“…Compared with the heterogeneity in PD-L1 expression, immune in ltrated cell-based scoring system could better re ect the immune status of the TME, thus more accurately identifying the population with stronger immune activity against tumor cells [35]. Besides, there was no apparent correlation between the level of immune cell in ltration and that of PD-L1 expression in the TME.…”