The role of glycan-lectin interactions in the tumor microenvironment: immunosuppression regulators of colorectal cancer

Abstract

Colorectal cancer (CRC) is a common malignant tumour and a serious global health issue. Glycosylation, a type of posttranslational modification, has been extensively studied in relation to cancer growth and metastasis. Aberrant glycosylation alters how the immune system in the microenvironment perceives the tumour and drives immune suppression through glycan-binding receptors. Interestingly, specific glycan signatures can be regarded as a new pattern of immune checkpoints. Lectins are a group of proteins that exhibit high affinity for glycosylation structures. Lectins and their ligands are found on endothelial cells (ECs), immune cells and tumour cells and play important roles in the tumour microenvironment (TME). In CRC, glycan-lectin interactions can accelerate immune evasion promoting the differentiation of tumour-associated M2 macrophages, altering T cell, dendritic cell (DC), natural killer (NK) cell, and regulatory T (Treg) cell activity to modify the functions of antigen-presenting cells functions. Here, we review our current knowledge on how glycan-lectin interactions affect immune-suppressive circuits in the TME and discuss their roles in the development of more effective immunotherapies for CRC.

Keywords: Colorectal cancer glycosylation; glycan-lectin interactions; immunotherapy; tumour microenvironment.

Figure 1

Schematic representation of CRC microenvironment. The TME is composed of various components, including ECM, endothelial cells and immune cells (neutrophil, macrophage, dendritic cell, NK cell, mast cell, regulatory T cell). Those components secrete soluble and insoluble factors, facilitate communication between tumor cells and their surroundings, regulate the development and progression of CRC. Created with BioRender.com.

Figure 2

Aberrant glycosylation patterns in CRC. A. Four types of N-glycans frequently altered in CRC are shown as high-mannose, pauci-mannose, hybrid-type and β-1,6-branching(poly-)LacNAc core-fucosylation. B. O-glycan structures in CRC frequently exhibit the truncated Tn, T and sialylated Tn antigen (sTn). C. The Lewis antigens encompass Lewis X/A and Lewis Y/B structures. Created with BioRender.com.

Figure 3

The diagram of lectin-mediated networks in CRC. Glycan-lectin mediated interactions take place between CRC cells and endothelial cells or immune cells in TME. The diverse molecular interactions highlight the intricate network that influences the progression and immune response of CRC. Created with BioRender.com.

Figure 4

The glycan-lectin axis in CRC immunotherapy via N-glycan removal and cellular immunotherapy. A. Removal N-glycan of Siglec-15 by PNGase-F contributes to an effective antitumour response. B. Removing N-glycosylation via KF facilitates immune recognition by DC-SIGN-expressing immune cells. C. The NKG2D-DAP12 complex recognizes the ligand on CRC cells, activates NK cells and promotes the antitumour process.

Figure 5

The glycan-lectin axis in CRC immunotherapy via blocking tumour-associated glycan-lectin interactions. A, B. NEU4 and hsa-miR-370 inhibit the attachment of sLea and sLex to E-selectin. C. C-3-substituted N,N0-diacetyllactosamine glycomimetics hinder the binding of cancer cells and epithelial cells via galectin-3-ASF interaction. D. Galectosyl prevents the growth and metastasis of CRC cells by inhibiting galectin-3. E. Anti-galectin-9 leads to an increased frequency of CD8 T cells and Treg cells. F. TDG or G1KD blocks the binding of galectin-1 with CD44 and CD306, increases the expression of CD4+ and CD8+ cells and prevents CRC lung metastasis.