Siglec Signaling in the Tumor Microenvironment

Abstract

Sialic acid-binding immunoglobulin-like lectins (Siglecs) are a family of receptors that recognize sialoglycans – sialic acid containing glycans that are abundantly present on cell membranes. Siglecs are expressed on most immune cells and can modulate their activity and function. The majority of Siglecs contains immune inhibitory motifs comparable to the immune checkpoint receptor PD-1. In the tumor microenvironment (TME), signaling through the Siglec-sialoglycan axis appears to be enhanced through multiple mechanisms favoring tumor immune evasion similar to the PD-1/PD-L1 signaling pathway. Siglec expression on tumor-infiltrating immune cells appears increased in the immune suppressive microenvironment. At the same time, enhanced Siglec ligand expression has been reported for several tumor types as a result of aberrant glycosylation, glycan modifications, and the increased expression of sialoglycans on proteins and lipids. Siglec signaling has been identified as important regulator of anti-tumor immunity in the TME, but the key factors contributing to Siglec activation by tumor-associated sialoglycans are diverse and poorly defined. Among others, Siglec activation and signaling are co-determined by their expression levels, cell surface distribution, and their binding preferences for cis- and trans-ligands in the TME. Siglec binding preference are co-determined by the nature of the proteins/lipids to which the sialoglycans are attached and the multivalency of the interaction. Here, we review the current understanding and emerging conditions and factors involved in Siglec signaling in the TME and identify current knowledge gaps that exist in the field.

Whole-cell tumor vaccines desialylated to uncover tumor antigenic Gal/GalNAc epitopes elicit anti-tumor immunity

“…Sialoglycans interact with Siglec-9 colocalized with the TCR-CD3 complex to inhibit TCR-mediated cell activation via recruitment of SHP-1 by ITIM phosphorylation to reduce ZAP 70 phosphorylation [ 57 ]. In addition, sialoglycans as alternative ligands of CD28 bind to CD80 on APCs, attenuating co-stimulatory signals of antigen-mediated activation of T cells [ 54 ].…”

Differential Immune Checkpoint and Ig-like V-Type Receptor Profiles in COVID-19: Associations with Severity and Treatment

“…Regarding our data about immune changes to corticosteroids, it is noteworthy the expression of sialic acid-binding immunoglobulin-type lectins (Siglecs) on monocyte cells. Targeting Siglecs has recently emerged as a promising therapeutic strategy in cancer [ 49 , 50 , 51 , 52 ]. In our study, we found that expression of both Siglec-3 (CD33) and Siglec-5 (CD170) increased after corticosteroid treatment.…”

Targeted nanomedicines remodeling immunosuppressive tumor microenvironment for enhanced cancer immunotherapy

“…Aberrant glycosylation is a universal hallmark of cancer cells, commonly characterized by anomalous expression and glycosylation of mucins, abnormal branching of N-glycans, and increased expression of sialoglycans on proteins and lipids 98 , 99 . Sialic acid-binding immunoglobulin-like lectins (Siglecs) expressed on most immune cells are receptors for tumor-cell-derived sialoglycans, and the signaling through the sialoglycan-Siglec axis is similar to the PD-1/PD-L1 signaling, which stifles the anti-tumor immunity and brings about immunosuppressive TME 100 , 101 , 102 . Hitherto few targeted nanomedicines interfering with the sialoglycan-Siglec immune checkpoint have been brought up, it is a potential approach for enhancing cancer immunotherapy.…”