Re-Expression of Poly/Oligo-Sialylated Adhesion Molecules on the Surface of Tumor Cells Disrupts Their Interaction with Immune-Effector Cells and Contributes to Pathophysiological Immune Escape

Abstract

Glycans linked to surface proteins are the most complex biological macromolecules that play an active role in various cellular mechanisms. This diversity is the basis of cell–cell interaction and communication, cell growth, cell migration, as well as co-stimulatory or inhibitory signaling. Our review describes the importance of neuraminic acid and its derivatives as recognition elements, which are located at the outermost positions of carbohydrate chains linked to specific glycoproteins or glycolipids. Tumor cells, especially from solid tumors, mask themselves by re-expression of hypersialylated neural cell adhesion molecule (NCAM), neuropilin-2 (NRP-2), or synaptic cell adhesion molecule 1 (SynCAM 1) in order to protect themselves against the cytotoxic attack of the also highly sialylated immune effector cells. More particularly, we focus on α-2,8-linked polysialic acid chains, which characterize carrier glycoproteins such as NCAM, NRP-2, or SynCam-1. This characteristic property correlates with an aggressive clinical phenotype and endows them with multiple roles in biological processes that underlie all steps of cancer progression, including regulation of cell–cell and/or cell–extracellular matrix interactions, as well as increased proliferation, migration, reduced apoptosis rate of tumor cells, angiogenesis, and metastasis. Specifically, re-expression of poly/oligo-sialylated adhesion molecules on the surface of tumor cells disrupts their interaction with immune-effector cells and contributes to pathophysiological immune escape. Further, sialylated glycoproteins induce immunoregulatory cytokines and growth factors through interactions with sialic acid-binding immunoglobulin-like lectins. We describe the processes, which modulate the interaction between sialylated carrier glycoproteins and their ligands, and illustrate that sialic acids could be targets of novel therapeutic strategies for treatment of cancer and immune diseases.

The vertebrate sialylation machinery: structure-function and molecular evolution of GT-29 sialyltransferases

“…Other sialylated structures that show increased levels in cancer include the serological cancer-biomarker sialyl-Lewis a (CA19.9; sLe a : Neu5Ac α2,3Galβ1,3[Fuc α1,4]GlcNAc) and the selectin ligand sialyl-Lewis x (sLe x : Neu5Ac α2,3Gal β1,4[Fuc α1,3]GlcNAc) which correlate with poor patient survival [ 62 – 65 ], the α2,3- or α2,6-linked sialic acid to N -acetyllactosamine (SLN) on N -glycosylproteins like cell receptors [ 66 ]. Solid tumor cells express hypersialylated neural cell adhesion molecule (NCAM), neuropilin-2 (NRP-2), or synaptic cell adhesion molecule 1 (SynCAM 1) to protect themselves from the immune effector cells [ 67 ]. Gangliosides like GM3, GM2, GD3 and GD2 are found in normal human tissues and are overexpressed in different cancer like lung cancer, melanoma, neuroblastoma, and breast cancer, in which they mediate cell proliferation, tumor growth and cancer cell migration [ 68 ].…”

“…These sialylated TACA possess immunomodulatory properties and dendritic cells (DCs) are capable of sense them and stimulate naive T cells, thereby initiating the adaptive immune response [ 67 , 73 ]. Siglecs are a family of 15 human cell surface receptors [ 74 ] that are primarily expressed by cells of the immune system, with the exception of most T cells.…”

Targeting Tumor Glycans for Cancer Therapy: Successes, Limitations, and Perspectives

“…For example, PSA-NCAM favors direct binding to fibroblast growth factor 2 (FGF2) and brain-derived neurotrophic factor (BDNF), thus supporting cellular growth and survival [297]. Moreover, polysialylated NCAM, NRP-2, and SynCAM 1 can stimulate various growth factor receptors in cancer cells, promoting oncogenesis via tyrosine kinase pathways, and immune escape of tumor cells by the interaction of PSA with inhibitory siglecs and protecting them from cytotoxicity [298].…”

Aberrant Sialylation in Cancer: Therapeutic Opportunities

“…Of particular interest, 2,8-disialic structures have been shown to be ligands for Siglec-7 and Siglec-9 and may act as glycoimmune checkpoints in cancer [ 100 , 101 ]. ST8SIA2 and ST8SIA4 are polysialyltransferases producing polysialylated cell adhesion molecules, which are re-expressed during cancer progression [ 134 , 136 , 137 ]. ST8SIA2 correlates with tumour progression in non-small-cell lung cancer [ 138 ] and has been linked to tumour invasion and metastasis [ 139 , 140 ].…”