Impact of Epithelial-Mesenchymal Transition on the Immune Landscape in Breast Cancer.

Fatima-Zohra Khadri,Marianne Samir Makboul Issac,Louis Arthur Gaboury

doi:10.3390/cancers13205099

Fatima-Zohra Khadri, Marianne Samir Makboul Issac + Show 1 more

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https://doi.org/10.3390/cancers13205099

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Abstract

Simple SummaryThe process of epithelial–mesenchymal transition (EMT) is thought to influence breast cancer tumor progression by affecting both tumor cells and the tumor microenvironment (TME). We aimed to study the impact of EMT-related markers on a breast cancer cohort and specifically analyze the involvement of Snail, Twist, ZEB1, N-cadherin, Vimentin, GRHL2, E-cadherin, and EpCAM and their respective outcome on both immune infiltration of the TME and clinicopathological features. The inflammatory infiltrate was more often associated with poorly differentiated carcinomas including triple-negative breast cancer (TNBC). The altered pattern of protein expression of epithelial markers markedly influenced the magnitude of the inflammatory infiltrate found in the TME. Overall, our data highlight the potential beneficial association of the EMT signature with the immune inflammatory response. This may open new avenues for rational decision making in the clinical use of immunotherapy in subsets of breast cancer patients, specifically TNBC.The impact of epithelial–mesenchymal transition (EMT) signature on the immune infiltrate present in the breast cancer tumor microenvironment (TME) is still poorly understood. Since there is mounting interest in the use of immunotherapy for the treatment of subsets of breast cancer patients, it is of major importance to understand the fundamental tumor characteristics which dictate the inter-tumor heterogeneity in immune landscapes. We aimed to assess the impact of EMT-related markers on the nature and magnitude of the inflammatory infiltrate present in breast cancer TME and their association with the clinicopathological parameters. Tissue microarrays were constructed from 144 formalin-fixed paraffin-embedded invasive breast cancer tumor samples. The protein expression patterns of Snail, Twist, ZEB1, N-cadherin, Vimentin, GRHL2, E-cadherin, and EpCAM were examined by immunohistochemistry (IHC). The inflammatory infiltrate in the TME was assessed semi-quantitatively on hematoxylin and eosin (H&E)-stained whole sections and was characterized using IHC. The inflammatory infiltrate was more intense in poorly differentiated carcinomas and triple-negative carcinomas in which the expression of E-cadherin and GRHL2 was reduced, while EpCAM was overexpressed. Most EMT-related markers correlated with plasma cell infiltration of the TME. Taken together, our findings reveal that the EMT signature might impact the immune response in the TME.

Highlights

Breast cancer is a highly heterogenous and complex disease characterized by a wide range of pathological and clinical features, unique morphological characteristics, distinct molecular subtypes, and varying responses to treatment [1]
We determined the clinical–pathological characteristics of the cohort, which included 144 breast cancer cases. Most of these cases were diagnosed as infiltrating ductal carcinomas (87.5%), while fewer cases were classified as invasive lobular carcinomas (9.7%)
To explore the potential role of epithelial–mesenchymal transition (EMT) as it relates to immune infiltration of the tumor microenvironment, we studied whether the levels of protein expression of the mesenchymal and epithelial EMT-related markers were associated with the extent of the inflammatory infiltrate

Summary

Introduction

Breast cancer is a highly heterogenous and complex disease characterized by a wide range of pathological and clinical features, unique morphological characteristics, distinct molecular subtypes, and varying responses to treatment [1]. Tumor progression is thought to be driven by the process of epithelial–mesenchymal transition (EMT), which enables epithelial cells to acquire mesenchymal features [2,3]. EMT is a multistep dynamic process allowing carcinoma cells to reside in various phenotypic states along the epithelial–mesenchymal (E–M) spectrum [7,8]. It is a reversible process, insofar as cells which undergo EMT can undergo MET [8,9]; this dynamic reversibility has been coined epithelial-to-mesenchymal plasticity [10]. Previous work on breast cancers indicated that EMT is one of the most crucial biological processes inducing stem-cell properties [11]. The aggressive hybrid double-positive CD24+ /CD44+ E/M cells display enhanced plasticity, metastatic capability, and stemness when compared to the fully epithelial CD24+ /CD44−

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