The essential microenvironmental role of oligomannoses specifically inserted into the antigen-binding sites of lymphoma cells.

There are 2 mandatory features added sequentially en route to classical follicular lymphoma (FL): first, the t(14;18) translocation, which upregulates BCL2, and second, the introduction of sequence motifs into the antigen-binding sites of the B-cell receptor (BCR), to which oligomannose-type glycan is added. Further processing of the glycan is blocked by complementarity-determining region-specific steric hindrance, leading to exposure of mannosylated immunoglobulin (Ig) to the microenvironment. This allows for interaction with the local lectin, dendritic cell-specific ICAM-3-grabbing nonintegrin (DC-SIGN), expressed by tissue macrophages and follicular dendritic cells. The major function of DC-SIGN is to engage pathogens, but this is subverted by FL cells. DC-SIGN induces tumor-specific low-level BCR signaling in FL cells and promotes membrane changes with increased adhesion to VCAM-1 via proximal kinases and actin regulators but, in contrast to engagement by anti-Ig, avoids endocytosis and apoptosis. These interactions appear mandatory for the early development of FL, before the acquisition of other accelerating mutations. BCR-associated mannosylation can be found in a subset of germinal center B-cell-like diffuse large B-cell lymphoma with t(14;18), tracking these cases back to FL. This category was associated with more aggressive behavior: both FL and transformed cases and, potentially, a significant number of cases of Burkitt lymphoma, which also has sites for N-glycan addition, could benefit from antibody-mediated blockade of the interaction with DC-SIGN.