Extracellular vesicles shed by follicular lymphoma B cells promote polarization of the bone marrow stromal cell niche

Abstract

Follicular Lymphoma (FL) originates in the lymph nodes (LN) and infiltrates bone marrow (BM) early in the course of the disease. BM FL B cells are characterized by a lower cytological grade, a decreased proliferation, and a specific phenotypic and subclonal profile. Mesenchymal stromal cells (MSC) obtained from FL BM display a specific gene expression profile (GEP), including enrichment for a lymphoid-stromal cell signature, and an increased capacity to sustain FL B-cell growth. However, the mechanisms triggering the formation of the medullar FL permissive stromal niche have not been yet identified. In the current work, we demonstrated that FL B cells produced extracellular vesicles (EVs) that could be internalized by BM-MSC, making them more efficient to support FL B-cell survival and quiescence. Accordingly, EVs purified from FL BM plasma activated TGF-b dependent and independent pathways in BM-MSC, modified their GEP, triggering an upregulation of factors classically associated with hematopoietic stem cell niche, including CXCL12 or angiopoietin-1. Moreover, we provided the first characterization of BM FL B-cell GEP, allowing the definition of the landscape of molecular interactions they could engage with EV-primed BM-MSC. This work identified FL-derived EVs as putative mediators of BM stroma polarization and supported further investigation of their clinical interest for targeting the crosstalk between BM-MSC and malignant B cells.

B cell/stromal cell crosstalk in health, disease, and treatment: Follicular lymphoma as a paradigm

“…In agreement, BM FL B cells are also characterized by a lower cytological grade, a decreased proliferation, a modified phenotype with reduced CD10 expression, and an altered gene expression profile compared with LN FL B cells 68,69. Moreover, somatic hypermutation analysis and targeted deep sequencing have demonstrated that different FL B-cell subclones could be detected within LN versus BM, and suggest that FL originates in the LN and infiltrates BM early in the course of the disease, allowing further accumulation of BM-specific mutations [69][70][71].…”

“…This discrepancy has been recently solved by the demonstration that FL B cells produce extracellular vesicles that could be internalized by BM stromal cells, making them more efficient to support BM FL B-cell survival and quiescence, at least in part through the production of CXCL12. 68 This study further suggests that differences in LN versus BM FL stromal cell phenotypes and mechanisms of reprogramming could drive locally specific patterns of molecular interactions with malignant B cells and contribute to tumor spatial heterogeneity. Interestingly, TGFβ signaling was identified as one of the underlying pathway supporting BM stromal cell activation by FL B cell-derived extracellular vesicles.…”

“…67 However, gene expression profile analysis has underlined key differences in the phenotype of FL-CAFs within BM and LN niches. 68 be analyzed once, at the diagnosis, making it difficult to infer the direct impact of each single genetic event on B-cell/TME crosstalk over the course of the disease. To fill this gap, genetically engineered mouse models have been proposed in the past few years, studying how the deregulation of a single genetic target synergizes with BCL2 overexpression to promote FL-like tumors.…”

“…104 Yet, FL B cell transcriptomic profile within a single biopsy dynamically spans a continuum of transitional states between proliferating GC-like and quiescent memorylike states, with rare cells carrying a plasma cell-like profile. 107 68 . This discrepancy has been recently solved by the demonstration that FL B cells produce extracellular vesicles that could be internalized by BM stromal cells, making them more efficient to support BM FL B-cell survival and quiescence, at least in part through the production of CXCL12.…”

“…Interestingly, TGFβ signaling was identified as one of the underlying pathway supporting BM stromal cell activation by FL B cell-derived extracellular vesicles. 68 A scRNA-seq study comparing distant FL LN from the same patients further highlights a specific correlation between site-to-site tumor heterogeneity and Tfh cell abundance, raising the question of the underlying stromal cell functional features. 106 Having discussed how malignant B cells and their stromal niche dynamically co-evolve to support FL initiation and progression, a remaining bullet point is the question of the clinical consequences of this crosstalk on patient behavior and treatment.…”