Coelho, V. et al. Glycosylation of surface Ig creates a functional bridge between human follicular lymphoma and microenvironmental lectins. Proc. Natl Acad. Sci. USA 107, 18587-18592

Molecular Immunology Group, Cancer Sciences Division, University of Southampton, School of Medicine, Southampton SO16 6YD, United Kingdom.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 10/2010; 107(43):18587-92. DOI: 10.1073/pnas.1009388107
Source: PubMed


Surface Ig (sIg) of follicular lymphoma (FL) is vital for tumor cell survival. We found previously that the Ig in FL is unusual, because the variable region genes carry sequence motifs for N-glycan addition. These are introduced by somatic mutation and are tumor specific. Unexpectedly, added glycans terminate at high mannose, suggesting a potentially important interaction of FL cells with mannose-binding lectins of the innate immune system. We have now identified mannosylated IgM at the surface of primary lymphoma cells. Recombinant lectin domains of the mannose receptor (MR) or DC-SIGN bind mannosylated Igs in vitro and bind to FL cells, signaling sIgM-associated increases in intracellular Ca(2+). Lectins also bind to normal B cells but fail to signal. In contrast, anti-Ig signaled similarly in both FL and normal B cells. Mannosylation patterns were mimicked by FL Ig-derived single-chain Fvs (scFv), providing probes for potential receptors. Mannosylated scFv bound specifically to the lectin domains of the MR and DC-SIGN and blocked signaling. Mannosylated scFv also bound to DC-SIGN on the surface of dendritic cells. This unique lymphoma-specific interaction of sIg with lectins of innate immunity reveals a potential route for microenvironmental support of tumor cells, mediated via the key B-cell receptor.

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    • "These signals might vary with SHM of V regions, which probably modulate interactions of malignant cells with various endogenous ligands. Indeed, N-glycosylation sites carrying high-mannose glycans and created by SHM within V domains are a frequent feature of follicular lymphoma cells, and may promote B cell interactions with lectins such as DC-SIGN [108]. The BCR Ig class might also somehow control the phenotype of B cell malignant proliferations. "
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    ABSTRACT: Survival and phenotype of normal and malignant B lymphocytes are critically dependent on constitutive signals by the B cell receptor (BCR) for antigen. In addition, either antigen ligation of the BCR or various mitogenic stimuli result in B cell activation and induction of activation-induced deaminase (AID). AID activity can in turn mediate somatic hypermutation (SHM) of immunoglobulin (Ig) V regions and also deeply remodel the Ig heavy chain locus through class switch recombination (CSR) or locus suicide recombination (LSR). In addition to changes linked to affinity for antigen, modifying the class/isotype (i.e. the structure and function) of the BCR or suddenly deleting BCR expression also modulates the fate of antigen-experienced B cells.
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    • "Another potential TAM-mediated pathway in FL is BCR signaling. In fact, whereas a recent study suggests that BCR from a subset of FL patients recognize self-antigens potentially retained on the surface of FDC [97], the majority of FL B cells express mannosylated BCR able to interact with C-type lectins DC-SIGN (CD209) and Mannose Receptor (CD206) independently of antigens [15] [16]. CD209 and CD206 are known to be upregulated on M2 macrophages and on TAM in solid tumors [98], a situation mirrored in FL by the overexpression of IL-4 by T FH [45]. "
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    ABSTRACT: Follicular lymphoma (FL) results from the malignant transformation of germinal center B cells and is characterized by recurrent genetic alterations providing a direct growth advantage or facilitating interaction with tumor microenvironment. In agreement, accumulating evidences suggest a dynamic bidirectional crosstalk between FL B cells and surrounding non-malignant cells within specialized tumor niches in both invaded lymph nodes and bone marrow. Infiltrating stromal cells, macrophages, and T/NK cell subsets either contribute to anti-tumor immune response, or conversely form a tumor supportive network promoting FL B cell survival, growth, and drug resistance. This review depicts the phenotypic heterogeneity and functional plasticity of the most important FL cell partners and describes their complex interplay. We also unravel how malignant B cells recruit and subvert accessory immune and stromal cells to trigger their polarization towards a supportive phenotype. Based on these observations, innovative therapeutic approaches have been recently proposed, in order to benefit from local anti-tumor immunity and/or to selectively target the protective cell niche.
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    • "Glycans added to these motifs are atypical in terminating at high mannose that interact with C-type lectins on the surface of surrounding cells and trigger BCR engagement. This functional bridge could mimic for continuous antigen stimulation to promote survival of FL cells (Coelho et al., 2010). About 30% of FL finally transform into aggressive diffuse large B cell lymphomas (DLBCL) that are less dependent on their microenvironment. "
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    ABSTRACT: Follicular lymphoma (FL) is the prototypical model of indolent B cell lymphoma displaying a strong dependence on a specialized cell microenvironment mimicking normal germinal center. Within malignant cell niches in invaded lymph nodes and bone marrow, external stimuli provided by infiltrating stromal cells make a pivotal contribution to disease development, progression, and drug resistance. The crosstalk between FL B cells and stromal cells is bidirectional, causing activation of both partners. In agreement, FL stromal cells exhibit specific phenotypic, transcriptomic, and functional properties. This review highlights the critical pathways involved in the direct tumor-promoting activity of stromal cells but also their role in the organization of FL cell niche through the recruitment of accessory immune cells and their polarization to a B cell supportive phenotype. Finally, deciphering the interplay between stromal cells and FL cells provides potential new therapeutic targets with the aim to mobilize malignant cells outside their protective microenvironment and increase their sensitivity to conventional treatment.
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