The (Sialyl) Tn antigen: Contributions to immunosuppression in gastrointestinal cancers

Abstract

Cellular signaling pathways are intricately regulated to maintain homeostasis. During cancer progression, these mechanisms are manipulated to become harmful. O-glycosylation, a crucial post-translational modification, is one such pathway that can lead to multiple isoforms of glycoproteins. The Tn (GalNAc-O-Ser/Thr) and Sialyl Tn (STn; Neu5Ac-GalNAc-O-Ser/Thr) antigens resulting from the incomplete synthesis of fully branched O-glycan chains on proteins contribute to disease progression in the pancreas and other gastrointestinal cancers. The tumor microenvironment (TME) is a major constituent of tumors and a key modulator of their behavior. Multiple cellular and secretory components of the TME dictate the development and metastasis of tumors. Immune cells like macrophages, natural killer (NK) cells, dendritic cells, B and T lymphocytes are a part of the tumor "immune" microenvironment (TIME). The expression of the Tn and STn antigens on tumors has been found to regulate the function of these immune cells and alter their normal antitumor cytotoxic role. This is possible through multiple cell intrinsic and extrinsic signaling pathways, elaborated in this review. Studying the interaction between Tn/STn antigens and the TIME of gastrointestinal cancers can help develop better and more robust therapies that can counteract immunosuppressive mechanisms to sensitize these tumors to anticancer therapies.

Keywords: STn antigen; Tn antigen; gastrointestinal tumour; glycosylation; immune cells; pancreas-adenocarcinoma; tumor microenvironment (TME).

Figure 1

Formation of truncated O-glycans in tumors modulates cell-intrinsic behavior and interactions with the tumor immune microenvironment. (A). O-glycosylation in human cells involves highly regulated sequential reactions catalyzed by glycosyltransferases. (B). Mechanisms mediating loss of O-glycan chain extension (mentioned in red) facilitate neoplastic transformation, increase oncogenic signaling cascades, the epithelial-to-mesenchymal transition process, and compromise death receptor stability to evade apoptosis. The Tn/STn antigens interact with macrophage-galactose lectin (MGL) and CD206 (mannose receptor), expressing tumor-associated macrophages (TAMs); natural killer (NK) cells; and monocytic dendritic cells - preventing their maturation, leading to an overall immunosuppressed microenvironment. [ppGalNAc-T, polypeptide-GalNActransferase; C1GalT1, core1 β3-galactosyltransferase; COSMC, Core1-Specific-Molecular-Chaperone; C2GnT, core2 β1,6 N-acetylglucosaminyltransferase; β3GnT6, β-1,3-N-Acetylglucosaminyltransferase; ST6GalNAc-1, α2,6 sialyltransferase; ST3Gal-1, α2,3 sialyltransferase; PDAC, pancreatic ductal adenocarcinoma].

Figure 2

Tumor cell STn-specific interactions with immune cells. Cancer cells overexpress the STn antigen and interact with Siglec receptors on immune cells and activate their intracellular ITIMs (immunoreceptor tyrosine-based inhibitory motifs). Siglec-9 on NK cells (and monocytes, not shown here) bind with STn antigens present on PDAC and ovarian tumor cells and cause disruption of NK cell-mediated tumor cytotoxicity. Siglec-10 expressing tumor associated macrophages (TAMs) bind the STn antigen on hepatocellular carcinoma cells, leading to upregulation of immune checkpoints and overall immune suppression in the tumor microenvironment (TME). Siglec-15 expressing TAMs in the PDAC TME bind STn antigen on the tumor and such Siglec-15: STn binding overrides the immunoreceptor tyrosine-based activation motif (ITAM) based signaling via Siglec-15 and instead mediates M2-like macrophage polarization, bringing about heavy immunosuppression.