Sialoglycans and Siglecs Can Shape the Tumor Immune Microenvironment

Aberrant sialic acid sugar expression is commonly found in different cancer types and immune cells express immunomodulatory Siglec receptors that can recognize these sialic acids in humans and mice. Recently, high expression of Siglecs was found on several immune cells within the tumor microenvironment (TME). Recent studies, using human samples and mouse models, indicate that sialoglycan–Siglec interactions in the TME can suppress effector immune cell activity and modulate myeloid cell functions, thus contributing to tumor immune evasion and sustained tumor growth. The individual contribution of the 14 Siglec family members to immune evasion and their precise sialoglycan ligands in the TME remain to be elucidated. Sialoglycans and Siglecs might represent immune ‘checkpoints’ that should be further explored as potential targets for cancer immunotherapy. Sialic acid sugar-carrying glycans, sialoglycans, are aberrantly expressed on many tumor cells and have emerged as potent regulatory molecules involved in creating a tumor-supportive microenvironment. Sialoglycans can be recognized by sialic acid-binding immunoglobulin-like lectins (Siglecs), a family of immunomodulatory receptors. Most mammalian Siglecs transmit inhibitory signals comparable with the immune checkpoint inhibitor programmed death protein 1 (PD-1), but some are activating. Recent studies have shown that tumor cells can exploit sialoglycan–Siglec interactions to modulate immune cell function, contributing to an immunosuppressive tumor microenvironment (TME). Interference with sialoglycan synthesis or sialoglycan–Siglec interactions might improve antitumor immunity. Many questions regarding specificity, signaling, and regulatory function of sialoglycan–Siglec interactions remain. We posit that sialoglycans and Siglecs present as potential glyco-immune ‘checkpoints’ for cancer immunotherapy. Sialic acid sugar-carrying glycans, sialoglycans, are aberrantly expressed on many tumor cells and have emerged as potent regulatory molecules involved in creating a tumor-supportive microenvironment. Sialoglycans can be recognized by sialic acid-binding immunoglobulin-like lectins (Siglecs), a family of immunomodulatory receptors. Most mammalian Siglecs transmit inhibitory signals comparable with the immune checkpoint inhibitor programmed death protein 1 (PD-1), but some are activating. Recent studies have shown that tumor cells can exploit sialoglycan–Siglec interactions to modulate immune cell function, contributing to an immunosuppressive tumor microenvironment (TME). Interference with sialoglycan synthesis or sialoglycan–Siglec interactions might improve antitumor immunity. Many questions regarding specificity, signaling, and regulatory function of sialoglycan–Siglec interactions remain. We posit that sialoglycans and Siglecs present as potential glyco-immune ‘checkpoints’ for cancer immunotherapy. synthetic fluorinated sialic acid mimetic that blocks sialic acid expression by inhibiting sialyltransferase activity. destruction of antibody-coated target cells by effector immune cells. immune cells capable of processing and presenting antigens to lymphocytes. engineered antibodies with two distinct binding sites. enzyme that activates sialic acids for incorporation into sialoglycans. the sequence of uptake, processing, and presentation of extracellular antigens on MHC I by DCs to activate CD8+ T cells. complement inhibiting protein that recognizes sialoglycans. highly diverse structures composed of different sugar molecules attached to glycoproteins and glycolipids. glycan analogs mimicking the structure of a glycan but with different biological effects. uridine diphosphate (UDP)-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase, a bifunctional enzyme involved in sialic acid biosynthesis. the dynamic process of the host immune system that prevents development of primary tumors and/or favors tumor immune evasion by shaping tumor immunogenicity or attenuation of antitumor immunity, respectively. conserved amino acid sequence in the cytoplasmic part of activating immune receptors, such as CD3. conserved amino acid sequence in the cytoplasmic part of immune inhibitory receptors, such as PD-1. lipid bilayer particles suitable, for example, for in vivo targeting and drug administration. glycoprotein with heavy O-glycosylation, overexpressed in many epithelial cancers. heterogeneous population of myeloid cells, associated with poor prognosis in cancer patients, that suppress effector immune cells. immunodeficient strain, lacking T cells, B cells, and NK cells. mouse CD8+ T cells expressing a transgenic TCR recognizing chicken ovalbumin (OVA 257–264) presented on MHC I. mouse CD4+ T cells expressing a transgenic TCR recognizing chicken ovalbumin (OVA 323–339) presented on MHC II. glycan-binding adhesion receptors [endothelial (E)-, leukocyte (L)-, platelet (P)-selectin] involved in lymphocyte homing. family of negatively charged sugars that cap glycans. family of immunomodulatory receptors, expressed in the immune system as well as in other tissues, that specifically bind to sialic acids. enzymes that cleave sialic acids off sialoglycans. glycans containing sialic acids. tumor-associated glycan containing sialic acid. gene encoding the Golgi-membrane transporter that transports cytidine-5′-monophospho-N-acetylneuraminic acid (CMP-sialic acid) into the Golgi. family of pattern-recognition receptors of the innate immune system recognizing pathogens. prominent in the TME; they generally promote tumor growth. tumor surrounding containing various cell types (tumor cells, endothelial cells, immune cells, fibroblasts etc.), extracellular matrix components, and soluble factors.