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

Pandey, S.; Mourcin, Frédéric; Marchand, Tony; Nayar, Saba; Guirriec, Marion; Pangault, Céline; Monvoisin, Céline; Amé-Thomas, Patricia; Guilloton, Fabien; Dulong, Joëlle; Coles, Mark; Fest, Thierry; Mottok, Anja; Barone, Francesca; Tarte, Karin

doi:10.1182/blood-2016-08-737239

Cited by 73 publications

(101 citation statements)

References 60 publications

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“…First, they could contribute to tumor B-cell recruitment and adhesion to protective cell niches. An upregulation of CXCL12 has been recently highlighted in LN and BM FL-CAFs and contributes to migration, adhesion, and activation of FL B cells that harbor a CXCR4 pos CXCR5 pos CCR7 lo phenotype [47]. Moreover, VCAM-1/CD106, the ligand of 41 (VLA-4) integrin, has been involved in GC B-cell lymphoma growth and resistance to the anti-CD20 antibody Rituximab [50].…”

Section: Mechanisms Of Stromal Cell Protumoral Activitymentioning

confidence: 99%

“…FL B cells exhibit the general hallmark of centrocytes and are strongly dependent on direct interaction with a GC-like microenvironment including Tfh, myeloid cells, and stromal cells while developing efficient immune escape mechanisms[44,45]. The protumoral role of tumor-infiltrating lymphoid stromal cells in FL has been highlighted by the identification of FRC-and FDC-like cells ectopically induced within invaded bone marrow (BM) where they are found admixed with malignant B cells[46,47]. In addition, despite strong differences in cell composition and organization, BM-and LN-FL niches display common stromal cell phenotype and extracellular matrix composition features including deregulation of the matricellular protein secreted protein acidic and rich in cysteine (SPARC), involved in collagen deposition and organization[48].…”

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confidence: 99%

“…overexpression of CCL2, IL-8, and CXCL12, suggesting an imprinting of stromal cells by the tumor context[47,55,58].Whatever their origin, the mechanisms underlying the differentiation of FL-CAFs are of utmost significance considering their potential as therapeutic targets. FL B cells could directly contribute to the activation of the FRC meshwork within invaded LN and BM, as highlighted by their capacity to trigger in vitro the commitment of mesenchymal precursors into FRC-like phenotype and their overexpression of CCL2 and IL-8 in a TNF-dependent manner[49,55,58].…”

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confidence: 99%

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Impact of B cell/lymphoid stromal cell crosstalk in B-cell physiology and malignancy

Lamaison

Tarte

2019

Immunology Letters

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Highlights-Lymphoid stromal cells form a heterogeneous and plastic cell compartment -Follicular and extrafollicular stromal cells contribute to normal B-cell activation -FL-CAFs exhibit specific phenotypic and transcriptomic features -FL B cells and their immune microenvironment trigger FL-CAF differentiation -FL-CAFs support directly malignant B-cell growth and organize tumor cell niche Abstract Stromal cells have been considered for a long time essentially as a structural component organizing tissue architecture, including those of secondary lymphoid organs. More recently, highly specialized stromal cell subsets were shown to differentially organize immune cell recruitment, survival, and differentiation within lymph nodes. In particular, mature B cells interact with different lymphoid stromal cell networks through bidirectional interactions involving cell-cell contact and soluble factors. Follicular lymphoma (FL) is the paradigm of a B-cell malignancy dependent on a lymphoid-like microenvironment supporting tumor cell growth, drug resistance, and clonal evolution. This review provides an overview of our current knowledge of lymphoid stromal cell heterogeneity and functions in normal B-cell activation. In addition, we also depict the dynamic and plasticity of FL cancer-associated fibroblasts, the mechanisms underlying their key role within FL permissive niches, and their potential as therapeutic targets in this still fatal malignancy.

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Section: Mechanisms Of Stromal Cell Protumoral Activitymentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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Impact of B cell/lymphoid stromal cell crosstalk in B-cell physiology and malignancy

Lamaison

Tarte

2019

Immunology Letters

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“…In homeostasis, lymph nodes express high levels of endogenous podoplanin (7), which increases upon in vivo immunization (18). Interestingly, follicular lymphoma-bearing lymph nodes show decreased podoplanin expression (19). The molecular mechanisms controlling these changes in podoplanin expression are not fully understood.…”

Section: Introductionmentioning

confidence: 99%

Fibroblastic Reticular Cell Response to Dendritic Cells Requires Coordinated Activity of Podoplanin, CD44 and CD9

Winde

Makris

Millward

et al. 2019

Preprint

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Lymph node expansion is pivotal during immune activation. It is controlled by interactions between CLEC-2 hi migratory dendritic cells and podoplanin + fibroblastic reticular cells (FRCs) resulting in rapid loss of actomyosin contractility permitting FRC spreading. Podoplanin is an inflammatory marker in many pathologies, reported to facilitate both contractility and cell protrusions. However, how podoplanin expression is regulated, and how this one membrane protein can elicit these opposing phenotypes is unknown. We report that CLEC-2 binding to FRCs induces transcriptional upregulation of podoplanin, increasing surface protein expression. Further, we find that tetraspanin CD82 is required for trafficking of podoplanin to the plasma membrane. At the cell surface, podoplanin elicits multiple functions, balanced by its membrane binding partners hyaluronan receptor CD44 and tetraspanin CD9. FRCs lacking expression of both CD44 and CD9 are hypercontractile, and upon binding to CLEC-2 hi dendritic cells, both CD44 KO and CD9 KO FRCs exhibit defective protrusion formation and fail to spread. Podoplanin co-localises with CD44 or CD9 in distinct membrane domains, and both CD44 and CD9 are required for FRCs to spread in response to dendritic cells, however they control formation of cell protrusions via different and complimentary mechanisms. In vivo, surface expression levels of podoplanin, CD44 and CD9 are upregulated on T-cell zone FRCs in the early phase of lymph node expansion. Our data support a model whereby podoplanin resides in distinct plasma membrane domains, and that CLEC-2 binding serves as a molecular switch to change podoplanin function. Podoplanin | CD44 | CD9 | CD82 | Tetraspanins | Fibroblastic reticular cell | Lymph node Correspondence: s.acton@ucl.ac.uk de Winde et al. | bioRχiv | October 3, 2019 | 1-2

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“…IL‐4 is known to have critical effector and homeostatic effects on lymphocytes, including protecting B cells from apoptosis, inducing IgG1 and IgE production, polarization of CD4 + T cells to a Th2 phenotype. For nonlymphocytes, it has been recently suggested that IL‐4 acts directly on human mesenchymal progenitors and downregulates gp38 on stromal cells lines, acting as a B‐cell extrinsic mechanism to modulate the Tfh/Tfh‐like‐ stroma crosstalk in follicular lymphoma . Given the relevance of lymphocyte and stromal cell population in lymphoid organs, we sought to determine the function of IL‐4 in peripheral lymph nodes.…”

Section: Discussionmentioning

confidence: 99%

IL‐4 promotes stromal cell expansion and is critical for development of a type‐2, but not a type 1 immune response

et al. 2019

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IL‐4 is critical for differentiation of Th2 cells and antibody isotype switching, but our work demonstrated that it is produced in the peripheral LN under both Type 2, and Type 1 conditions, raising the possibility of other functions. We found that IL‐4 is vital for proper positioning of hematopoietic and stromal cells in steady state, and the lack of IL‐4 or IL‐4Rα correlates with disarrangement of both follicular dendritic cells and CD31+ endothelial cells. We observed a marked disorganization of B cells in these mice, suggesting that the lymphocyte‐stromal cell axis is maintained by the IL‐4 signaling pathway. This study showed that absence of IL‐4 correlates with significant downregulation of Lymphotoxin alpha (LTα) and Lymphotoxin beta (LTβ), critical lymphokines for the development and maintenance of lymphoid organs. Moreover, immunization of IL‐4 deficient mice with Type 2 antigens failed to induce lymphotoxin production, LN reorganization, or germinal center formation, while this process is IL‐4 independent following Type 1 immunization. Additionally, we found that Type 1 antigen mediated LN reorganization is dependent on IFN‐γ in the absence of IL‐4. Our findings reveal a role of IL‐4 in the maintenance of peripheral lymphoid organ microenvironments during homeostasis and antigenic challenge.

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

Cited by 73 publications

References 60 publications

Impact of B cell/lymphoid stromal cell crosstalk in B-cell physiology and malignancy

Impact of B cell/lymphoid stromal cell crosstalk in B-cell physiology and malignancy

Fibroblastic Reticular Cell Response to Dendritic Cells Requires Coordinated Activity of Podoplanin, CD44 and CD9

IL‐4 promotes stromal cell expansion and is critical for development of a type‐2, but not a type 1 immune response

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