DC-SIGN binding to the surface immunoglobulin oligomannose-type glycans promotes follicular lymphoma cell adhesion and survival

ABSTRACT: The occupation of the surface immunoglobulin antigen-binding site by oligomannose-type glycans (sIg-Mann) is a tumor-specific posttranslational modification of classic follicular lymphoma (FL). SIg-Mann switches binding from antigen to dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin (DC-SIGN), which is expressed on interfollicular macrophages and FL-associated follicular dendritic cells (FDCs). The interaction with DC-SIGN induces reorganization of sIg-Mann in wider and less dense clusters than anti-Ig, consistent with inefficient DC-SIGN-induced endocytosis and low-level intracellular signaling. However, ligand-specific cell clusters form between sIg-Mann-expressing lymphoma cells and DC-SIGN-expressing cells, raising the need to understand the functional consequences of the interaction of DC-SIGN with sIg-Mann on primary FL cells. This engagement induces adhesion of FL cells to vascular cell adhesion molecule 1 (VCAM-1) via B-cell receptor-proximal kinases and actin regulators in a fashion similar to anti-Ig but without initiating apoptosis in vitro. Instead, antibody blockade of sIg-Mann contact with DC-SIGN, expressed on FDC-derived YK6/SIGN cells, inhibits adhesion and survival of primary FL cells in vitro. These data highlight that the specific interaction with DC-SIGN induces FL cell adhesion to VCAM-1, likely allowing FL cell retention in the lymph node and FL cell survival. Adhesion and survival are inhibited by an anti-DC-SIGN blocking antibody, indicating a new early therapeutic approach against FL retention and survival in adaptive tumor-tissue niches.