The Tn antigen promotes lung tumor growth by fostering immunosuppression and angiogenesis via interaction with Macrophage Galactose-type lectin 2 (MGL2)

Tn is a tumor-associated carbohydrate antigen that constitutes both a diagnostic tool and an immunotherapeutic target. It originates from interruption of the mucin O-glycosylation pathway through defects involving, at least in part, alterations in core-1 synthase activity, which is highly dependent on Cosmc, a folding chaperone. Tn antigen is recognized by the Macrophage Galactose-type Lectin (MGL), a C-type lectin receptor present on dendritic cells and macrophages. Specific interactions between Tn and MGL shape anti-tumoral immune responses by regulating several innate and adaptive immune cell programs. In this work, we generated and characterized a variant of the lung cancer murine cell line LL/2 that expresses Tn by mutation of the Cosmc chaperone gene (Tn(+) LL/2). We confirmed Tn expression by lectin glycophenotyping and specific anti-Tn antibodies, verified abrogation of T-synthase activity in these cells, and confirmed its recognition by the murine MGL2 receptor. Interestingly, Tn+ LL/2 cells were more aggressive in vivo, resulting in larger and highly vascularized tumors than those generated from wild type Tn(-) LL/2 cells. In addition, Tn(+) tumors exhibited an increase in CD11c(+) F4/80(+) cells with high expression of MGL2, together with an augmented expression of IL-10 in infiltrating CD4(+) and CD8(+) T cells. Importantly, this immunosuppressive microenvironment was dependent on the presence of MGL2(+) cells, since depletion of these cells abrogated tumor growth, vascularization and recruitment of IL-10(+) T cells. Altogether, our results suggest that expression of Tn in tumor cells and its interaction with MGL2-expressing CD11c(+)F4/80(+) cells promote immunosuppression and angiogenesis, thus favoring tumor progression.

Automated summary

Tn antigen, originating from tumor cells, interacts with the MGL receptor to promote immunosuppression and angiogenesis, ultimately favoring tumor progression.