Cracking the Breast Cancer Glyco-Code through Glycan-Lectin Interactions: Targeting Immunosuppressive Macrophages.

Nuno Lopes,Viviana G Correia,Angelina S Palma,Catarina Brito

doi:10.3390/ijms22041972

Abstract

The immune microenvironment of breast cancer (BC) is composed by high macrophage infiltrates, correlated with the most aggressive subtypes. Tumour-associated macrophages (TAM) within the BC microenvironment are key regulators of immune suppression and BC progression. Nevertheless, several key questions regarding TAM polarisation by BC are still not fully understood. Recently, the modulation of the immune microenvironment has been described via the recognition of abnormal glycosylation patterns at BC cell surface. These patterns rise as a resource to identify potential targets on TAM in the BC context, leading to the development of novel immunotherapies. Herein, we will summarize recent studies describing advances in identifying altered glycan structures in BC cells. We will focus on BC-specific glycosylation patterns known to modulate the phenotype and function of macrophages recruited to the tumour site, such as structures with sialylated or N-acetylgalactosamine epitopes. Moreover, the lectins present at the surface of macrophages reported to bind to such antigens, inducing tumour-prone TAM phenotypes, will also be highlighted. Finally, we will discuss and give our view on the potential and current challenges of targeting these glycan-lectin interactions to reshape the immunosuppressive landscape of BC.

Highlights

Breast cancer (BC) is one of the most prevalent cancer types, especially among women, with over 2 million new cases estimated for 2020 (24.5% from all new cases) [1]
Endocrine and targeted therapies have significantly improved the prognostic of hormone positive and human epidermal growth receptor 2 (HER2)-positive breast cancer, respectively, whereas for patients with triple negative BC (TNBC), scarce therapeutic options are available [2]
Through analysis of gene expression signatures, the authors further observed that M2-protumorigenic macrophages were highly represented in the C2 cluster, associated with the basal-like BC subtype and tumour infiltrating lymphocytes (TIL) were enriched in C3, associated with the claudin-low subtype

Summary

Introduction

Breast cancer (BC) is one of the most prevalent cancer types, especially among women, with over 2 million new cases estimated for 2020 (24.5% from all new cases) [1]. Macrophages within the tumour site have been reported to recognize tumour-specific glycans, which triggers their polarization into immunosuppressive phenotypes [9] These tumour-associated macrophages (TAM) are described to suppress other immune cells and remodel the surrounding microenvironment, playing a key role in tumour progression (as detailed in Section 2) [10]. Major players in this glycan recognition are the glycan-binding receptors displayed at the immune cell surface, generally termed lectins. We will review the current state on built-up of immunosuppressive microenvironments in BC, summarizing current knowledge on the role of glycan-mediated interactions between BC cells and immune cells, with a focus on TAM. We will discuss the potential and the current challenges to unravel these interactions as new targets for immunotherapies

Tumour-Associated Macrophages within the Breast Cancer Microenvironment

Altered Glycosylation Patterns in Breast Cancer

Findings

Glycan-Lectin Interactions