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.

A Comprehensive Analysis of Tn and STn Antigen Expression in Esophageal Adenocarcinoma

“…As glycans have evolved into essential components within homeostatic circuits, functioning as precise modulators of immunological responses, they emerge as potential molecular targets for intentionally modulating immune tolerance and activation across a spectrum of pathological scenarios. The recent review article emphasizes the significant role of Tn and STn antigen expression in gastrointestinal tumors in contributing to immunosuppression [49]. The focal point remains on innate immune system cells, specifically those expressing glycan-binding receptors like CD301 (MGL) [50], Siglec-4, -5, -14, and -15 [51], and potentially other receptors selectively interacting with tumor O-glycans.…”

Unraveling the role of C1GALT1 in abnormal glycosylation and colorectal cancer progression

“…This connection implies that the appearance of Tn and sTn within cells could be one of the initial steps in the development of colorectal cancer ( 34 ). Moreover, the neo- or over-expression of Tn, sTn, and T antigens is not limited to colorectal cancer but occurs in many types of cancer, including gastric, colon, breast, lung, esophageal, prostate, and endometrial cancer ( 60 , 61 ). This widespread occurrence underscores the significance of these antigens in cancer biology, particularly in promoting tumor metastasis.…”

Sialylation: A Cloak for Tumors to Trick the Immune System in the Microenvironment

“…ST6GalNAc I, which adds Neu5Ac to O-linked GalNAc residues to form sialyl-Tn (STn), is particularly significant [ 76 ]. Evidence suggests that the overexpression of STn is associated with poor clinical prognosis in a wide range of cancer types [ 27 , 77 ], making it a well-known tumor-associated carbohydrate antigen. One functional study found that ST6GalNAc I can promote tumor growth and metastasis and is related to cancer cell stemness [ 78 ].…”