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.
Highlights
The cornerstone of a healthy immune system is the ability to distinguish “self ” from “nonself,” to mount a response to “nonself ” while minimizing the reactivity to “self ” [1]
The observations that tumor marker gangliosides (TMGs) can inhibit antibody production and lymphocyte proliferation were first made decades ago [127, 128]. This is increasingly relevant in modern immunotherapy as it is possible that the high failure rate of conventional immune checkpoint blockade (ICB) therapy in melanoma is associated with high GD2/GD3 expression, a hypothesis that we are evaluating experimentally
A lack of memory potentially translates into short-lived anti-tumor responses, but this may be overcome by using the chimeric antigen receptors (CAR) γδ T cell therapy in multiple treatment cycles
Summary
The cornerstone of a healthy immune system is the ability to distinguish “self ” from “nonself,” to mount a response to “nonself ” while minimizing the reactivity to “self ” [1]. A tumor originates from cells that remain mostly “self.” identifying meaningful differences between pathological and healthy cells has been difficult in the dynamic tumor microenvironment (TME). The erratic pattern of gene expression, altered metabolism, deregulated signaling pathways, and often high mutational burden results in the presentation of neoantigens on the surface of tumor cells. These novel antigens can be recognized by both the innate and adaptive arms of the immune system, this response can be counteracted by the TME via immunoediting, immunoevasion, and immunosuppression
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