Insertion of atypical glycans into the tumor antigen-binding site identifies DLBCLs with distinct origin and behavior.
Chiodin G., Allen JD., Bryant D., Rock P., Martino EA., Valle-Argos B., Duriez PJ., Watanabe Y., Henderson I., Blachly JS., McCann KJ., Strefford JC., Packham G., Geijtenbeek TB., Figdor C., Wright G., Staudt LM., Burack R., Bowden T., Crispin M., Stevenson FK., Forconi F.
Glycosylation of the surface immunoglobulin variable region is a remarkable follicular lymphoma-associated feature rarely seen in normal B cells. Here, we define a subset of diffuse large B-cell lymphomas (DLBCL) which acquire N-glycosylation sites selectively in the immunoglobulin (Ig) complementary-determining-regions (CDR) of the antigen-binding sites. Mass-spectrometry and X-ray crystallography demonstrate how the inserted glycans are stalled at oligomannose-type structures due to burial in the CDR loops. Acquisition of sites occurs in ~50% of germinal center B-cell-like DLBCL, mainly of the genetic EZB subtype, irrespective of IGHV-D-J use. This markedly contrasts with the activated B-cell-like DLBCL Ig, which rarely has sites in the CDR, and appears not to acquire oligomannose-type structures. Acquisition of CDR-located acceptor sites associates with mutations of epigenetic regulators and BCL2 translocations, indicating an origin shared with follicular lymphoma. Within the EZB subtype, these sites associate with more rapid disease progression and with significant gene-set enrichment of the B-cell receptor, PI3K/AKT/MTORC1, glucose metabolism, and MYC signaling pathways, particularly in the fraction devoid of MYC translocations. The oligomannose-type glycans on the lymphoma cells interact with the candidate lectin DC-SIGN, mediating low-level signals, and lectin-expressing cells form clusters with lymphoma cells. Both clustering and signaling are inhibited by antibodies specifically targeting the DC-SIGN carbohydrate-recognition-domain. Oligomannosylation of the tumor immunoglobulin is a post-translational modification that readily identifies a distinct GCB-DLBCL category with more aggressive clinical behavior, and could be a potential precise therapeutic target via antibody-mediated inhibition of the tumor Ig interaction with DC-SIGN-expressing M2-polarized macrophages.