Heterogeneity of tumour‐infiltrating lymphocytes in breast cancer and its prognostic significance

Althobiti, Maryam; Aleskandarany, Mohammed A.; Joseph, Chitra; Toss, Michael S.; Mongan, Nigel P.; Diez-Rodriguez, Maria; Nolan, Christopher C.; Ashankyty, Ibraheem; Ellis, Ian O.; Green, Andrew; Rakha, Emad A.

doi:10.1111/his.13695

Cited by 66 publications

(52 citation statements)

References 40 publications

(84 reference statements)

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“…Most previous studies focused on the prognostic effect of individual cell subsets [24][25][26]. Ali et al confirmed a positive correlation between B cells and prognosis and clustered breast cancer patients into 8 types according to immune cell subsets distribution [25].…”

Section: Discussionmentioning

confidence: 99%

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

Jiang¹,

Pan²,

Xu³

et al. 2020

J. Cancer

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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.

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Section: Discussionmentioning

confidence: 99%

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

Jiang¹,

Pan²,

Xu³

et al. 2020

J. Cancer

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“…Manipulation of this interaction is a fast-growing field, and several immune checkpoint inhibitors have been described in several solid cancers including BC which show highly promising results for therapy [52, 53]. There is sufficient evidence to demonstrate that moderate and intense inflammation is associated with improved prognosis in triple-negative (TN) and HER2-positive BC [54-56]. TILs comprise several types of immune cells, including tumour-promoting and tumour-suppressing cells.…”

Section: Interaction With the Surrounding Microenvironmentmentioning

confidence: 99%

Molecular Complexity of Lymphovascular Invasion: The Role of Cell Migration in Breast Cancer as a Prototype

et al. 2020

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Lymphovascular invasion (LVI) is associated with poor outcome in breast cancer (BC); however, its underlying mechanisms remain ill-defined. LVI in BC develops through complex molecular pathways involving not only the interplay with the surrounding microenvironment along with endothelial cells lining the lymphovascular spaces but also changes in the malignant epithelial cells with the acquisition of more invasive and migration abilities. In this review, we focus on the key features that enable tumour cell detachment from the primary niche, their migration and interaction with the surrounding microenvironment as well as the crosstalk with the vascular endothelial cells, which eventually lead to intravasation of tumour cells and LVI. Intravascular tumour cell survival and migration, their distant site extravasation, stromal invasion and growth are part of the metastatic cascade. Cancer cell migration commences with loss of tumour cells' cohesion initiating the invasion and migration processes which are usually accompanied by the accumulation of specific cellular and molecular changes that enable tumour cells to overcome the blockades of the extracellular matrix, spread into surrounding tissues and interact with stromal cells and immune cells. Thereafter, tumour cells migrate further via interacting with lymphovascular endothelial cells to penetrate the vessel wall leading ultimately to intravasation of cancer cells. Exploring the potential factors influencing cell migration in LVI can help in understanding the underlying mechanisms of LVI to identify targeted therapy in BC.

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“…Survival data were available and prospectively maintained, including (i) BC-specific survival (BCSS), defined as the duration (in months) from the date of the primary surgical treatment to the time of death from BC, and (ii) distant metastasis-free survival (DMFS), defined as the duration (in months) from surgery to the first event of distant metastasis. 15,16 The mean follow-up period of the study cohort was 130 months, median was 120 months and the range was 239 months. Patients were uniformly treated based on tumour features, NPI and hormone receptor status.…”

Section: T U M O U R C H a R A C T E R I S T I C S O F T H E S T U D mentioning

confidence: 99%

The prognostic significance of ALDH1A1 expression in early invasive breast cancer

et al. 2020

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Aims Aldehyde dehydrogenase family 1 member A1 (ALDH1A1) is reportedly a key ALDH isozyme linked to the cancer stem cells (CSC) of many solid tumours, where it is involved in self‐renewal, differentiation and self‐protection. In this study, the prognostic significance of ALDH1A1 expression in early invasive breast cancer (BC) and its role as a BC stem cell (BCSC) were evaluated. Methods and results ALDH1A1 expression was assessed, using immunohistochemistry and tissue microarrays, in a large well‐characterised BC cohort. ALDH1A1 mRNA expression was also assessed at transcriptomic levels, utilising data from the Molecular Taxonomy of Breast Cancer International Consortium. The associations of ALDH1A1 with clinicopathological parameters, other stem cell markers and patient outcomes were determined. ALDH1A1 was expressed in 71% of BC cases at both the protein and mRNA levels. High ALDH1A1 expression was associated with poor prognostic features, including high grade, poor Nottingham Prognostic Index (NPI), lymph node metastasis and highly proliferative ER+ (luminal B) and triple‐negative (TNBC) subtypes. ALDH1A1 expression was positively correlated with the expression of CD44, CD24, TWIST, SOX9, EPCAM and CD133. The high immunoexpression of ALDH1A1 was significantly associated with poor BC‐specific survival (P < 0.001), and specifically in the luminal B and TNBC subtypes (P = 0.042 and P = 0.003, respectively). The immunoexpression of ALDH1A1 was an independent predictor of poor prognosis (P = 0.015). Conclusions ALDH1A1, as assessed using immunohistochemistry, seems to act as a BCSC marker associated not only with other BCSC markers but also with poor prognostic characteristics and poor outcomes, particularly in the luminal B and TNBC subtypes.

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Heterogeneity of tumour‐infiltrating lymphocytes in breast cancer and its prognostic significance

Abstract: Despite the heterogeneity of immune cell type components, average TILs in one full-face H&E-stained section reliably represent TILs in the whole tumour. TILs were associated with outcome in TNBC patients, as well as having prognostic significance for recurrent tumours.

Cited by 66 publications

References 40 publications

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

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

Molecular Complexity of Lymphovascular Invasion: The Role of Cell Migration in Breast Cancer as a Prototype

The prognostic significance of ALDH1A1 expression in early invasive breast cancer

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