Siglecs as Therapeutic Targets in Cancer

Abstract

Hypersialylation is a common post-translational modification of protein and lipids found on cancer cell surfaces, which participate in cell-cell interactions and in the regulation of immune responses. Sialic acids are a family of nine-carbon α-keto acids found at the outermost ends of glycans attached to cell surfaces. Given their locations on cell surfaces, tumor cells aberrantly overexpress sialic acids, which are recognized by Siglec receptors found on immune cells to mediate broad immunomodulatory signaling. Enhanced sialylation exposed on cancer cell surfaces is exemplified as “self-associated molecular pattern” (SAMP), which tricks Siglec receptors found on leukocytes to greatly down-regulate immune responsiveness, leading to tumor growth. In this review, we focused on all 15 human Siglecs (including Siglec XII), many of which still remain understudied. We also highlighted strategies that disrupt the course of Siglec-sialic acid interactions, such as antibody-based therapies and sialic acid mimetics leading to tumor cell depletion. Herein, we introduced the central roles of Siglecs in mediating pro-tumor immunity and discussed strategies that target these receptors, which could benefit improved cancer immunotherapy.

Myeloid CD169/Siglec1: An immunoregulatory biomarker in viral disease

“…The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/ fmed.2022.979373/full#supplementary-material SUPPLEMENTARY FIGURE 1 (a) Domain organization of CD169: CD169 belongs to the Ig-like Siglec superfamily, hence the designation Sialic acid-binding immunoglobulin-type lectins. Siglecs are a group of cell surface molecules, which can roughly be subdivided into highly conserved Siglecs, including CD169, and CD33-related Siglecs (24,70,71). CD169, being one of the largests representatives of its family, consists of 17 immunoglobulin domains, that are characteristically protruding in the peripheral extracellular space.…”

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.…”

The intriguing roles of Siglec family members in the tumor microenvironment

“…Additionally, Siglec-6 expression has been reported in AML blasts and B cells in subjects with chronic lymphocytic leukemia (CLL) [ 34 ] and mucosa-associated lymphoid tissue lymphoma [ 35 ]. As Siglec-6 mRNA and protein are not expressed in hematopoietic stem cells, they are novel targets for CAR-T-cell immunotherapy in CLL [ 20 , 23 ].…”

“…Therapeutic targeting of the Sia-Siglec axis is promising for the treatment of tumors because Siglecs are mostly expressed in immune cells and affect the TME. Currently, monoclonal antibodies (mAbs) targeting Siglecs are applied to deplete tumor cells via passive immunotherapy [ 20 ]. Most mAbs specifically bind a target antigen and neutralize or stimulate its activity; however, newer therapeutic strategies, such as immune checkpoint inhibition, and T-cell engaging therapies, such as bispecific T-cell engaging (BiTE) single-chain antibody constructs and chimeric antigen receptor (CAR) T cells, have shown remarkable efficacy in clinical trials [ 73 ].…”