DC-SIGN–expressing macrophages trigger activation of mannosylated IgM B-cell receptor in follicular lymphoma

Abstract

Key Points IgM+ FL B cells display a stronger BCR response than their GC B-cell counterpart despite significant BCR-related phosphatase activity. M2 macrophages trigger DC-SIGN–dependent cell adhesion and BCR activation in IgM+ FL B cells with a highly mannosylated BCR.

IL-4/CXCL12 loop is a key regulator of lymphoid stroma function in follicular lymphoma

“…19,53 In addition, IL-4 is also involved in the polarization of FL-infiltrating macrophages. 16 Altogether, these results highlight IL-4 as a key mediator and FL pathogenesis and T FH -stroma crosstalk as a new B-cell extrinsic mechanism that supports FL cell growth (supplemental Figure 11).…”

“…Chemokine receptor signaling also involved various components of the BCR signaling pathways, and both BTK and phosphoinositide 39-kinase isoform p110d (PI3Kd) inhibitors were shown to abrogate tumor cell migration toward stromal cell-derived CXCL12 in chronic lymphocytic leukemia (CLL). 35,36 We recently pointed out the efficacy of the BTK inhibitor ibrutinib in abolishing the crosstalk between FL B cells and tumor-associated macrophages, 16 but no study has been designed to decipher how ibrutinib or the PI3Kd inhibitor idelalisib could affect stroma/FL B-cell interactions. We first evaluated CXCR4 expression in FL.…”

“…In particular, IL-4 is a well-known inducer of dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin, a mannose-binding lectin recently implicated in the antigen-independent triggering of FL BCR by tumor-associated macrophages. 16 Whether IL-4 could modulate the properties of FL-infiltrating stromal cells has never been explored.…”

The Emerging Importance of IgG Fab Glycosylation in Immunity

“…These tumor-associated Fab glycans are highmannose structures, whereas the corresponding Fc glycans are complex-type biantennary glycans, confirming that the normal N-linked glycan-processing pathway is intact (6,47). Signaling through interactions between N-linked glycans on follicular lymphoma BCRs and lectins, such as DC-SIGN or mannose-binding lectin, at the surface of macrophages and dendritic cells may free these cells from dependence on Ag and may contribute to tumor cell persistence or growth (48,49). Some lectins from opportunistic pathogens, such as Pseudomonas aeruginosa and Burkholderia cenocepacia, can also interact with high-mannose BCR Fab glycans (50) (Fig.…”

Single-agent ibrutinib in relapsed or refractory follicular lymphoma: a phase 2 consortium trial

“…[5][6][7][8][9][10] Follicular lymphoma (FL) cells exhibit enhanced BCR activation via both antigen-dependent and -independent mechanisms. [11][12][13] In a phase 1 study of ibrutinib in relapsed B-cell malignancies, 6 (54%) of 11 patients with FL who received doses $2.5 mg/kg achieved an objective response. 14,15 The median duration of response (DOR) and progression-free survival (PFS) were 12.3 and 13.4 months, respectively.…”