Follicular lymphoma triggers phenotypic and functional remodeling of the human lymphoid stromal cell landscape

Mourcin, Frédéric; Verdière, Léa; Roulois, David; Amin, Rada; Lamaison, Claire; Sibut, Vonick; Thamphya, Brice; Pangault, Céline; Monvoisin, Céline; Huet, Sarah; Seffals, Marine; Baulande, Sylvain; Mechta‐Grigoriou, Fatima; Legoix, Patricia; Rossille, Delphine; Guirriec, Marion; Léonard, Simon; Cartron, Guillaume; Salles, Gilles; Fest, Thierry; Tarte, Karin

doi:10.1016/j.immuni.2021.05.019

Cited by 51 publications

(68 citation statements)

References 95 publications

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“…In addition, our study confirmed previous data by showing that LZ stromal FDCs express very high levels of the CD23 receptor (22,23). Complementing very recently published data from Cyster's team showing that FDC restricted IL-4 availability in the GC (24) and our work revealing the expression of IL-4 receptor and CD40 by FDCs (39), it is tempting to speculate that FDCs activate CD23 expression by trapping molecules produced by Tfh cells in the LZ and then titrating them. In such a case, the LZ B GC -cells require effective, lasting contact with Tfh cells for activation leading notably in B cells by the recruitment of the IL-4/STAT6 signaling and CD23 expression (19).…”

Section: Discussionsupporting

confidence: 90%

Committed Human CD23-Negative Light-Zone Germinal Center B Cells Delineate Transcriptional Program Supporting Plasma Cell Differentiation

et al. 2021

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B cell affinity maturation occurs in the germinal center (GC). Light-zone (LZ) GC B cells (BGC-cells) interact with follicular dendritic cells (FDCs) and compete for the limited, sequential help from T follicular helper cells needed to escape from apoptosis and complete their differentiation. The highest-affinity LZ BGC-cells enter the cell cycle and differentiate into PCs, following a dramatic epigenetic reorganization that induces transcriptome changes in general and the expression of the PRDM1 gene in particular. Human PC precursors are characterized by the loss of IL-4/STAT6 signaling and the absence of CD23 expression. Here, we studied the fate of human LZ BGC-cells as a function of their CD23 expression. We first showed that CD23 expression was restricted to the GC LZ, where it was primarily expressed by FDCs; less than 10% of tonsil LZ BGC-cells were positive. Sorted LZ BGC-cells left in culture and stimulated upregulated CD23 expression but were unable to differentiate into PCs – in contrast to cells that did not upregulate CD23 expression. An in-depth analysis (including single-cell gene expression) showed that stimulated CD23-negative LZ BGC-cells differentiated into plasmablasts and time course of gene expression changes delineates the transcriptional program that sustains PC differentiation. In particular, we identified a B cell proliferation signature supported by a transient MYC gene expression. Overall, the CD23 marker might be of value in answering questions about the differentiation of normal BGC-cells and allowed us to propose an instructive LZ BGC-cells maturation and fate model.

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Section: Discussionsupporting

confidence: 90%

Committed Human CD23-Negative Light-Zone Germinal Center B Cells Delineate Transcriptional Program Supporting Plasma Cell Differentiation

et al. 2021

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“…Whereas cell-intrinsic or TME-dependent NF-B activation is a well-described hallmark of B-NHL, FL tumor niche GEP was only recently found enriched for gene networks related to TGF signaling 54 . Moreover, TGF could contribute to the priming by FL B cells of BM-MSC and LN stromal cells into tumor-supportive stromal niche 12,55 . Finally, one study describes an upregulation and an activation of SMAD1 in malignant FL B cells 56 suggesting that TGF- signaling could play a major role in the interplay between B cells and stromal cells in FL.…”

Section: Discussionmentioning

confidence: 99%

“…Gene Set Enrichment Analysis (GSEA version 4.1.0) was used for the analysis of DOHH2 and HLY1 gene expression profile (GEP) to identify the gene sets that were enriched between two conditions. Results were then compared to those obtained by comparing the GEP of purified FL B cells and purified centrocyte (Affymetrix microarrays, purified centrocytes, GSE136248, n=5; purified FL B cells, GSE85233, n=10) 26 after Limma analysis with a FDR of 5% and an absolute fold change>1.5 12 .…”

Section: Rna-seq Analysismentioning

confidence: 99%

“…Conversely, TSC did not trigger GEP modifications reflecting cell proliferation inhibition in HLY1 in 2D nor 3D (data not shown). To further increase the relevance of our data, we analyzed the molecular pathways activated in purified FL B cells compared to purified normal centrocytes using already published Affymetrix microarray data 12,26 (Figure 6E). Interestingly, TNF/NF-B, hypoxia, and TGF belonged to the top pathways significantly enriched in FL GEP, as reported for DOHH2 maintained in 3D spheroids with TSC, suggesting that our spheroid culture model mimicked at least partly, the context of FL LN.…”

Section: Microencapsulated 3d Co-cultures Recapitulate Features Of Primary Fl B Cellsmentioning

confidence: 99%

“…In turn, FL cells modulate the phenotype and function of their surrounding microenvironment. In particular, FL-infiltrating stromal cells are engaged in a bidirectional crosstalk with malignant B cells within infiltrated lymph nodes (LN) and bone marrow [10][11][12] . Conversely DLBCL are less dependent on LN microenvironment but specific stromal signatures impact DLBCL prognosis 7,13,14 .…”

Section: Introductionmentioning

confidence: 99%

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A novel 3D culture model recapitulates primary FL B-cell features and promotes their survival

et al. 2021

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Non-Hodgkin B-cell lymphomas (B-NHL) mainly develop within lymph nodes (LN) as densely packed aggregates of tumor cells and their surrounding microenvironment, creating a tumor niche specific to each lymphoma subtypes. In vitro preclinical models mimicking biomechanical forces, cellular microenvironment, and 3D organization of B-cell lymphomas remain scarce, while all these parameters constitute key determinants of lymphomagenesis and drug resistance. Using a microfluidic method based on cell encapsulation inside permeable, elastic, and hollow alginate microspheres, we developed a new tunable 3D-model incorporating lymphoma B cells, extracellular matrix (ECM), and/or tonsil stromal cells (TSC). We revealed that under 3D confinement lymphoma B cells were able to form cohesive spheroids resulting from overexpression of ECM components. Moreover, lymphoma B cells and TSC dynamically formed self-organized 3D spheroids favoring spheroid growth. 3D culture induced resistance to classical chemotherapeutic agent doxorubicin, but not to BCL2 inhibitor ABT-199, identifying this approach as a relevant in vitro model to assess the activity of therapeutic agents in B-NHL. RNAseq analysis highlighted the synergy of 3D, ECM, and TSC in upregulating similar pathways in malignant B cells in vitro than those overexpressed in primary lymphoma cells in situ. Finally, our 3D model including ECM and TSC allowed long-term in vitro survival of primary follicular lymphoma B cells. In conclusion, we propose a new high throughput 3D model mimicking lymphoma tumor niche and making it possible to study the dynamic relationship between lymphoma B cells and their microenvironment and to screen new anti-cancer drugs.

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The survival grip–how cell adhesion promotes tumor maintenance within the microenvironment

Gardano,

Ferreira,

Le Roy

et al. 2024

FEBS Letters

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Cell adhesion is warranted by proteins that are crucial for the maintenance of tissue integrity and homeostasis. Most of these proteins behave as receptors to link adhesion to the control of cell survival and their expression or regulation are often altered in cancers. B‐cell malignancies do not evade this principle as they are sustained in relapsed niches by interacting with the microenvironment that includes cells and their secreted factors. Focusing on chronic lymphocytic leukemia and mantle cell lymphoma, this Review delves with the molecules involved in the dialog between the adhesion platforms and signaling pathways known to regulate both cell adhesion and survival. Current therapeutic strategies disrupt adhesive structures and compromise the microenvironment support to tumor cells, rendering them sensitive to immune recognition. The development of organ‐on‐chip and 3D culture systems, such as spheroids, have revealed the importance of mechanical cues in regulating signaling pathways to organize cell adhesion and survival. All these elements contribute to the elaboration of the crosstalk of lymphoma cells with the microenvironment and the education processes that allow the establishment of the supportive niche.

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Follicular lymphoma triggers phenotypic and functional remodeling of the human lymphoid stromal cell landscape

Cited by 51 publications

References 95 publications

Committed Human CD23-Negative Light-Zone Germinal Center B Cells Delineate Transcriptional Program Supporting Plasma Cell Differentiation

Committed Human CD23-Negative Light-Zone Germinal Center B Cells Delineate Transcriptional Program Supporting Plasma Cell Differentiation

A novel 3D culture model recapitulates primary FL B-cell features and promotes their survival

The survival grip–how cell adhesion promotes tumor maintenance within the microenvironment

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