Aiming for the Sweet Spot: Glyco-Immune Checkpoints and γδ T Cells in Targeted Immunotherapy

Abstract

Though a healthy immune system is capable of recognizing and eliminating emergent cancerous cells, an established tumor is adept at escaping immune surveillance. Altered and tumor-specific expression of immunosuppressive cell surface carbohydrates, also termed the “tumor glycocode,” is a prominent mechanism by which tumors can escape anti-tumor immunity. Given their persistent and homogeneous expression, tumor-associated glycans are promising targets to be exploited as biomarkers and therapeutic targets. However, the exploitation of these glycans has been a challenge due to their low immunogenicity, immunosuppressive properties, and the inefficient presentation of glycolipids in a conventional major histocompatibility complex (MHC)-restricted manner. Despite this, a subset of T-cells expressing the gamma and delta chains of the T-cell receptor (γδ T cells) exist with a capacity for MHC-unrestricted antigen recognition and potent inherent anti-tumor properties. In this review, we discuss the role of tumor-associated glycans in anti-tumor immunity, with an emphasis on the potential of γδ T cells to target the tumor glycocode. Understanding the many facets of this interaction holds the potential to unlock new ways to use both tumor-associated glycans and γδ T cells in novel therapeutic interventions.

Disrupting N-glycan expression on tumor cells boosts chimeric antigen receptor T cell efficacy against solid malignancies

“…Tumor cells display aberrant glycosylation, which manifests as a profoundly diverse extracellular glycan coat as compared to healthy cells. This coating, besides regulating fundamental biological events, may also negatively affect the magnitude of antitumor responses, either by masking neo-epitopes to immune cells or by interfering with immune cell functions ( 13 ). For instance, a tumor cell’s sialic acid might shut down natural killer activation and favor polarization of macrophages to an immunosuppressive M2 phenotype through binding to Siglec receptors ( 14 , 15 ).…”

Design of a Cytotoxic Neuroblastoma-Targeting Agent Using an Enzyme Acting on Polysialic Acid Fused to a Toxin

“…Given the heterogeneity within tumor tissue, it is likely that the uneven distribution of targeted toxin could result in partial removal of polysialic acid in many of the target cells, in contrast to the complete sweep seen in vitro. Tumor-associated antigens exposed by removal of the shielding polysialic acid layer could potentially make these cells more vulnerable to immune attack (48).…”

Insights into the Role of Sialylation in Cancer Metastasis, Immunity, and Therapeutic Opportunity

“…Thus, abnormal sialylation confers the immunosuppressive status to cancers. Additionally, interactions of sialoglycans and sialic acid-binding immunoglobulin-like lectins (Siglecs) are considered glyco-immune checkpoints for cancer [ 123 , 124 , 125 , 126 ]. α2,3-Sialylated glycans on tumor cells dictate the differentiation of monocytes into immunosuppressive macrophages through Siglec-7 and Siglec-9 signalings [ 127 , 128 ].…”