The C-type lectin MGL expressed by dendritic cells detects glycan changes on MUC1 in colon carcinoma

Abstract

The epithelial mucin MUC1 is a high molecular weight membrane glycoprotein frequently overexpressed and aberrantly glycosylated in adenocarcinoma. Mucins normally contain high amounts of O-linked carbohydrate structures that may influence immune reactions to this antigen. During malignant transformation, certain glyco-epitopes of MUC1, such as Tn-antigen, TF-antigen and their sialylated forms become exposed. The role of these glycan structures in tumor biology is unknown, but their presence is known to correlate with poor prognosis in several adenocarcinomas. We analyzed the potency of MUC1 containing Tn-antigens (MUC1-Tn) to target C-type lectins that function as carbohydrate recognition and uptake molecules on dendritic cells (DC). We identified the macrophage galactose type C-type lectin (MGL), expressed by both DC and macrophages, as the receptor for recognition and binding of MUC1-Tn. To validate the occurrence of MGL-MUC1 interactions in situ, we studied the binding of MGL to MUC1 in primary colon carcinoma tissue. Isolation of MUC1 out of colon carcinoma tissue showed strong binding activity to MGL. Interestingly, MGL binding to MUC1 was highly correlated to binding by the lectin Helix pomatia agglutinin (HPA), which is associated with poor prognosis in colorectal cancer. The detection of MGL positive cells in situ at the tumor site together with the modified glycosylation status of MUC1 to target MGL on DC suggests that MGL positive antigen presenting cells may play a role in tumor progression.

Cosmc is an essential chaperone for correct protein O-glycosylation

“…Tn expression is associated with poor prognosis, along with accelerated tumor progression and metastasis (1). Although the advantages for tumor cells carrying Tn antigen are not fully understood, binding of Tn antigen by a C-type lectin, termed MGL, on both dendritic cells and macrophages enhances tolerance to the tumor cells (34)(35)(36). Future studies using this animal model can explore whether Tn(+) cells or tissues become more susceptible to mutagenesis in the mosaic animals, and whether Tn(+) cells in vivo have survival and growth privileges.…”

Interactions of tumor cells with dendritic cells: balancing immunity and tolerance

“…87 Although the diversity and signaling mediated by these receptors remains to be clarified, engagement of these receptors by tumor cells may have major effects on antigen presentation. Some examples of potential CLR ligands expressed by tumor cells include muc1, which binds to the mannose receptor and galactose-type clectin 88 and the carcinoembryonic antigen (CEA), which binds to DC-SIGN. 89 Role of TOLL-like receptors.…”

Targeting of macrophage galactose‐type C‐type lectin (MGL) induces DC signaling and activation

“…Moreover, in vivo, MGL appears to play a crucial role in close proximity of the endothelial structures of lymph nodes and thymus, where iDCs are hampered in their migration activity until maturation [6]. In cancer, MGL has been described to enable DCs to sense glycosylation [17] and to selectively recognize tumor-associated glycoproteins [18]. The Tn-MUC1 glycoform represents one of the tumor-associated antigens (TAAs) studied as an MGL ligand.…”

“…The targeting of CLRs on DCs has recently acquired a great interest for cancer immunotherapy. Several authors have recently demonstrated that CLR targeting represents an optimal strategy to enhance antigen presentation by DCs, because CLRs are the designed receptors that can recognize endocytose glycans expressed by TAAs released during tumor progression [10,17,18]. Different approaches have been proposed to target CLRs in vivo and in vitro, such as antigen coupling to CLR-specific antibody and recombinant glycoproteins [28].…”