Melanoma tumour‐derived glycans hijack dendritic cell subsets through C‐type lectin receptor binding

• Published in: Immunology Vol. 171; no. 2; pp. 286 - 311
• Main Authors: Niveau, Camille, Sosa Cuevas, Eleonora, Roubinet, Benoît, Pezet, Mylène, Thépaut, Michel, Mouret, Stéphane, Charles, Julie, Fieschi, Franck, Landemarre, Ludovic, Chaperot, Laurence, Saas, Philippe, Aspord, Caroline
• Format: Journal Article
• Language: English
• Published: England Wiley Subscription Services, Inc 01.02.2024; Wiley
• Subjects: Cancer; Carbohydrates; Chemokines; Confocal microscopy; C‐type lectin receptor; DC subsets; Dendritic cells; Flow cytometry; fucose; Glycan; Glycolipids; Glycoproteins; Glycosylation; Immune checkpoint; Immune system; Immunity; Lectins; Life Sciences; Melanoma; Polysaccharides; Signal transduction; Toll-like receptors; Tumors; fucose; glycan; C-type lectin receptor; melanoma; DC subsets
• ISSN: 0019-2805; 1365-2567
• DOI: 10.1111/imm.13717

Dendritic cell (DC) subsets play a crucial role in shaping anti‐tumour immunity. Cancer escapes from the control immune system by hijacking DC functions. Yet, bases for such subversion are only partially understood. Tumour cells display aberrant glycan motifs on surface glycoproteins and glycolipids. Such carbohydrate patterns can be sensed by DCs through C‐type lectin receptors (CLRs) that are critical to shape and orientate immune responses. We recently demonstrated that melanoma tumour cells harboured an aberrant ‘glyco‐code,’ and that circulating and tumour‐infiltrating DCs from melanoma patients displayed major perturbations in their CLR profiles. To decipher whether melanoma, through aberrant glycan patterns, may exploit CLR pathways to mislead DCs and evade immune control, we explored the impact of glycan motifs aberrantly found in melanoma (neoglycoproteins [NeoGP] functionalised with Gal, Man, GalNAc, s‐Tn, fucose [Fuc] and GlcNAc residues) on features of human DC subsets (cDC2s, cDC1s and pDCs). We examined the ability of glycans to bind to purified DCs, and assessed their impact on DC basal properties and functional features using flow cytometry, confocal microscopy and multiplex secreted protein analysis. DC subsets differentially bound and internalised NeoGP depending on the nature of the glycan. Strikingly, Fuc directly remodelled the expression of activation markers and immune checkpoints, as well as the cytokine/chemokine secretion profile of DC subsets. NeoGP interfered with Toll like receptor (TLR)‐signalling and pre‐conditioned DCs to exhibit an altered response to subsequent TLR stimulation, dampening antitumor mediators while triggering pro‐tumoral factors. We further demonstrated that DC subsets can bind NeoGP through CLRs, and identified GalNAc/MGL and s‐Tn/ C‐type lectin‐like receptor 2 (CLEC2) as potential candidates. Moreover, DC dysfunction induced by tumour‐associated carbohydrate molecules may be reversed by interfering with the glycan/CLR axis. These findings revealed the glycan/CLR axis as a promising checkpoint to exploit in order to reshape potent antitumor immunity while impeding immunosuppressive pathways triggered by aberrant tumour glycosylation patterns. This may rescue DCs from tumour hijacking and improve clinical success in cancer patients. By exploring the impact of melanoma‐derived glycan motifs on features of human dendritic cell (DC) subsets, we revealed that cDC2s, cDC1s and pDCs differentially bind to and/or internalise glycans (neoglycoproteins functionalised with Gal, Man, GalNAc, s‐Tn, fucose [Fuc] and GlcNAc motifs). Some glycans exhibited a strong direct impact on DCs by directly modulating their basal activation and immune checkpoint profile, and triggered pro‐tumoral cytokine/chemokine production. Glycans also altered DC function and completely reshaped DC secretome upon Toll like receptor (TLR) stimulation. Our study highlights that melanoma, through a specific glycan signature, exploit the lectin pathway to hijack DC subsets and escape from immune control.