Insertion of atypical glycans into the tumor antigen-binding site identifies DLBCLs with distinct origin and behavior

DOI: 10.1182/blood.2021012052

Authors: Giorgia Chiodin (Cancer Research United Kingdom Southampton Centre) , Joel D. Allen (University of Southampton) , Dean J. Bryant (Cancer Research United Kingdom Southampton Centre) , Philip Rock (University of Rochester Medical Center) , Enrica A. Martino (ancer Research United Kingdom Southampton Centre; University of Catania) , Beatriz Valle-Argos (Cancer Research United Kingdom Southampton Centre) , Patrick J. Duriez (Cancer Research United Kingdom Southampton Centre) , Yasunori Watanabe (University of Oxford) , Isla Henderson (Cancer Research United Kingdom Southampton Centre) , James S. Blachly (The Ohio State University) , Katy J. Mccann (Cancer Research United Kingdom Southampton Centre) , Jonathan C. Strefford (Cancer Research United Kingdom Southampton Centre) , Graham Packham (Cancer Research United Kingdom Southampton Centre) , Teunis B. H. Geijtenbeek (University of Amsterdam) , Carl G. Figdor (Radboud University Medical Center) , George W. Wright (National Cancer Institute, National Institutes of Health) , Louis M. Staudt (National Cancer Institute, National Institutes of Health) , Richard Burack (University of Rochester Medical Center) , Thomas A. Bowden (University of Oxford) , Max Crispin (University of Southampton) , Freda K. Stevenson (Cancer Research United Kingdom Southampton Centre) , Francesco Forconi (Cancer Research United Kingdom Southampton Centre; University Hospital Southampton National Health Service Trust)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Blood , VOL 138 , PAGES 1570 - 1582

State: Published (Approved)
Published: October 2021
Diamond Proposal Number(s): 14744

Abstract: Glycosylation of the surface immunoglobulin (Ig) 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 (DLBCLs) that acquire N-glycosylation sites selectively in the Ig complementarity-determining regions (CDRs) of the antigen-binding sites. Mass spectrometry and X-ray crystallography demonstrate how the inserted glycans are stalled at oligomannose-type structures because they are buried in the CDR loops. Acquisition of sites occurs in ∼50% of germinal-center B-cell–like DLBCL (GCB-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 does not seem 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 are associated with more rapid disease progression and with significant gene set enrichment of the B-cell receptor, PI3K/AKT/MTORC1 pathway, 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 dendritic cell–specific intercellular adhesion molecule 3 grabbing non-integrin (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 Ig is a posttranslational modification that readily identifies a distinct GCB-DLBCL category with more aggressive clinical behavior, and it could be a potential precise therapeutic target via antibody-mediated inhibition of the tumor Ig interaction with DC-SIGN–expressing M2-polarized macrophages.

Diamond Keywords: Blood Cancer

Subject Areas: Biology and Bio-materials, Medicine


Instruments: I04-Macromolecular Crystallography

Added On: 10/01/2022 13:20

Discipline Tags:

Non-Communicable Diseases Health & Wellbeing Cancer Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)