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

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.

Gene-behavior theory: Behavior from nil to tangible glycosylation-implications for cancer prognosis and treatment strategies

“…Furthermore, dramatic changes were observed in protein glycosylation levels in gastrointestinal track tumors (esophageal, gastric, and colorectal cancers), thereby generating molecular fingerprints (Fernandes et al, 2020). Similar tumor-specific glycosylation findings were also identified in ovarian, cervical, and breast carcinoma (Hu et al, 2020;Sakata-Matsuzawa et al, 2021;Lopes et al, 2021;Xu et al, 2021).…”

Distinct cuproptosis patterns in hepatocellular carcinoma patients correlate with unique immune microenvironment characteristics and cell-cell communication, contributing to varied overall survival outcomes

“…Notably, T_memory and Macrophage_FCN1 + were significantly lower in the high-expression group compared to the low-expression group ( Figure 8F , Supplementary Table 7 ). Previous studies have highlighted the role of FCN + macrophages in recognizing and eliminating tumor cells by detecting abnormal glycosylation patterns on their surface ( 28 , 29 ). Additionally, the infiltration of T memory cells within tumors allows for quicker and stronger immune responses ( 30 ).…”

Identification of a prognostic risk-scoring model and risk signatures based on glycosylation-associated cluster in breast cancer

“…This often leads to tumor immune escape and immunomodulation. Therefore, the glycosylation-related signatures could affect tumor-immune cells’ connections within the tumor microenvironment ( Rodríguez et al, 2018 ; Lopes et al, 2021 ). In addition, a variety of recruited stomal components–transformed parenchyma and the associated stroma–are involved in tumor progression and response to treatment ( Arneth, 2019 ; Hanahan, 2022 ).…”