Colorectal cancer (CRC) is the third most prevalent
cancer type worldwide with a mortality rate of approximately 50%. Elevated cell-surface expression of truncated
carbohydrate structures such as
Tn antigen (GalNAcĪ±-Ser/Thr) is frequently observed during
tumor progression. We have previously demonstrated that the
C-type lectin macrophage
galactose-type
lectin (MGL), expressed by human antigen presenting cells, can distinguish healthy tissue from CRC through its specific recognition of
Tn antigen. Both MGL binding and oncogenic BRAF mutations have been implicated in establishing an immunosuppressive microenvironment. Here we aimed to evaluate whether MGL
ligand expression has prognostic value and whether this was correlated to BRAF(V600E) mutation status. Using a cohort of 386
colon cancer patients we demonstrate that high MGL binding to stage III
tumors is associated with poor disease-free survival, independent of
microsatellite instability or
adjuvant chemotherapy. In vitro studies using CRC cell lines showed an association between MGL
ligand expression and the presence of BRAF(V600E). Administration of specific BRAF(V600E) inhibitors resulted in decreased expression of MGL-binding
glycans. Moreover, a positive correlation between induction of BRAF(V600E) and MGL binding to epithelial cells of the gastrointestinal tract was found in vivo using an inducible BRAF(V600E) mouse model. We conclude that the BRAF(V600E) mutation induces MGL
ligand expression, thereby providing a direct link between oncogenic transformation and aberrant expression of immunosuppressive
glycans. The strong prognostic value of MGL
ligands in stage III
colon cancer patients, i.e. when
tumor cells disseminate to lymph nodes, further supports the putative immune evasive role of MGL
ligands in metastatic disease.