Stromal Cell Contribution to Human Follicular Lymphoma Pathogenesis

Mourcin, Frédéric; Pangault, Céline; Amin, Rada; Amé-Thomas, Patricia; Tarte, Karin

doi:10.3389/fimmu.2012.00280

Cited by 47 publications

(50 citation statements)

References 63 publications

(74 reference statements)

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“…2,[27][28][29] However, these parameters do not address the underlying microenvironment and bi-directional crosstalk between FL B-cells and stromal cells that may herald aggressive disease biology in advance of clinical presentation and deterioration. 30 Cytokines present within the tumor microenvironment appear to contribute to growth and survival of malignant cells and also ensures a continued inflammatory milieu recruiting reactive cells to lymphoma tissue. [31][32][33] Elevations in various cytokines have been reported as markers of aggressive lymphoma.…”

Section: Discussionmentioning

confidence: 99%

Elevated serum levels of IL-2R, IL-1RA, and CXCL9 are associated with a poor prognosis in follicular lymphoma

Mir¹,

Maurer²,

Ziesmer³

et al. 2015

Blood

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• Elevated IL-2R, IL-1RA, and CXCL9 are associated with shorter event-free survival in newly diagnosed FL, treated with chemoimmunotherapy.• Increased serum IL-12 and IL-1RA is associated with shorter event-free survival in patients who were observed or treated with rituximab alone.Serum cytokines and chemokines may reflect tumor biology and host response in follicular lymphoma (FL). To determine whether the addition of these biological factors may further refine prognostication, 30 cytokines and chemokines were measured in pretreatment serum specimens from newly diagnosed FL patients (n 5 209) and from 400 matched controls. Cytokine levels were correlated with clinical outcome in patients who were observed or received single agent rituximab, or those who received chemotherapy.Correlations with outcome in chemotherapy treated patients were further examined in a separate cohort of 183 South West Oncology Group (SWOG) patients and all patients were then included in a meta-analysis. Six cytokines were associated with outcome in the Molecular Epidemiology Resource (MER) after adjusting for the FL international prognostic index. In patients who were observed or treated with rituximab alone, increased serum IL-12 and interleukin 1 receptor antagonist (IL-1RA) (P 5 .005 and .02) were associated with a shorter event-free survival. In patients receiving chemotherapy, hepatocyte growth factor, IL-8, IL-1RA, and CXCL9 (P 5 .015, .048, .004, and .0005) predicted a shorter EFS. When the MER chemotherapy treated patients and SWOG patients were combined in a meta-analysis, IL-2R, IL-1RA, and CXCL9 (P 5 .013, .042, and .0012) were associated with a poor EFS. (Blood. 2015;125(6):992-998) Introduction Follicular lymphoma (FL) is the second most common non-Hodgkin lymphoma in the United States.1 While classified as an indolent B-cell lymphoma, the clinical course exhibits a spectrum based on the FL international prognostic index (FLIPI) score with a remarkable tendency for patients to relapse.2 The overall survival rate of patients with FL was previous reported as 75% at 5 years, and ranged from 71% at 10 years for patients with a FLIPI score between 0 to 1, and 36% for those with a FLIPI score of .3. Currently, the median survival of all newly diagnosed patients is approximately 9 years. 3Although the overall survival appears to have improved with advances in chemoimmunotherapy, the median event free survival (EFS) remains around 2 years for patients with advanced disease. 4 As a prognostic score, the FLIPI has several limitations. It focuses on clinical factors and does not take into account biological factors such as the tumor microenvironment and the host response. Indeed, some studies have found better prognostication of the very high-risk group with the international prognostic index (IPI) rather than with the FLIPI. 5,6 The FLIPI may potentially be further improved, particularly in the high-risk categories, if biological data are added. Gene expression profiling studies on pretreatment specimens from patients with FL hav...

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Section: Discussionmentioning

confidence: 99%

Elevated serum levels of IL-2R, IL-1RA, and CXCL9 are associated with a poor prognosis in follicular lymphoma

Mir¹,

Maurer²,

Ziesmer³

et al. 2015

Blood

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“…Further support for the hypothesis that indolent and aggressive lymphoma progression is also determined by the cellular microenvironment, in addition to genomic aberrations of the malignant cells 11,12 , is derived from gene expression profiling in diffuse large B-cell lymphomas. It has been shown that survival of these patients is strongly influenced by immune cell infiltration, fibrosis and angiogenesis, collectively grouped as stromal-1 and -2 signatures 13 .…”

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confidence: 97%

Dendritic cell-mediated survival signals in Eμ-Myc B-cell lymphoma depend on the transcription factor C/EBPβ

et al. 2014

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The capacity of dendritic cells (DCs) to regulate tumour-specific adaptive immune responses depends on their proper differentiation and homing status. Whereas DC-associated tumour-promoting functions are linked to T-cell tolerance and formation of an inflammatory milieu, DC-mediated direct effects on tumour growth have remained unexplored. Here we show that deletion of DCs substantially delays progression of Myc-driven lymphomas. Lymphoma-exposed DCs upregulate immunomodulatory cytokines, growth factors and the CCAAT/enhancer-binding protein b (C/EBPb). Moreover, Em-Myc lymphomas induce the preferential translation of the LAP/LAP* isoforms of C/EBPb. C/EBPb À/ À DCs are unresponsive to lymphoma-associated cytokine changes and in contrast to wild-type DCs, they are unable to mediate enhanced Em-Myc lymphoma cell survival. Antigen-specific T-cell proliferation in lymphoma-bearing mice is impaired; however, this immune suppression is reverted by the DC-restricted deletion of C/EBPb. Thus, we show that C/EBPb-controlled DC functions are critical steps for the creation of a lymphoma growth-promoting and -immunosuppressive niche.

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“…This could result from their cognate nature and ability to encounter antigen-laden FDCs. The preferred tumor cell localization in the FDC-rich GC light zone may also be due to the paracrine provision of growth-promoting factors ( 34,35 ). BCR engagement, as evidenced by activated BTK, and the receipt of growth factors could act differentially during tumor ontogeny and in a complementary manner.…”

Section: Research Articlementioning

confidence: 99%

“…4H ). Next, we mimicked cytokine and growth factor conditions that were suggested to support either GC B-cell proliferation or follicular B-cell lymphoma expansion ( 34,35 ). When supplemented, a substantial increase in cell proliferation was obtained for BAFF, CXCL12, Sonic hedgehog (SHH), hepatocyte growth factor (HGF), CXCL13, and IL15 ( Fig.…”

Section: Research Articlementioning

confidence: 99%

Access to Follicular Dendritic Cells Is a Pivotal Step in Murine Chronic Lymphocytic Leukemia B-cell Activation and Proliferation

et al. 2014

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In human chronic lymphocytic leukemia (CLL) pathogenesis, B-cell antigen receptor signaling seems important for leukemia B-cell ontogeny, whereas the microenvironment infl uences B-cell activation, tumor cell lodging, and provision of antigenic stimuli. Using the murine Eμ-Tcl1 CLL model, we demonstrate that CXCR5-controlled access to follicular dendritic cells confers proliferative stimuli to leukemia B cells. Intravital imaging revealed a marginal zone B cell-like leukemia cell traffi cking route. Murine and human CLL cells reciprocally stimulated resident mesenchymal stromal cells through lymphotoxin-β-receptor activation, resulting in CXCL13 secretion and stromal compartment remodeling. Inhibition of lymphotoxin/lymphotoxin-β-receptor signaling or of CXCR5 signaling retards leukemia progression. Thus, CXCR5 activity links tumor cell homing, shaping a survival niche, and access to localized proliferation stimuli. SIGNIFICANCE: CLL and other indolent lymphoma are not curable and usually relapse after treatment, a process in which the tumor microenvironment plays a pivotal role. We dissect the consecutive steps of CXCR5-dependent tumor cell lodging and LTβR-dependent stroma-leukemia cell interaction; moreover, we provide therapeutic solutions to interfere with this reciprocal tumor-stroma cross-talk. Cancer Discov; 4(12); 1448-65.

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Stromal Cell Contribution to Human Follicular Lymphoma Pathogenesis

Cited by 47 publications

References 63 publications

Elevated serum levels of IL-2R, IL-1RA, and CXCL9 are associated with a poor prognosis in follicular lymphoma

Elevated serum levels of IL-2R, IL-1RA, and CXCL9 are associated with a poor prognosis in follicular lymphoma

Dendritic cell-mediated survival signals in Eμ-Myc B-cell lymphoma depend on the transcription factor C/EBPβ

Access to Follicular Dendritic Cells Is a Pivotal Step in Murine Chronic Lymphocytic Leukemia B-cell Activation and Proliferation

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