Functional Alteration of the Lymphoma Stromal Cell Niche by the Cytokine Context: Role of Indoleamine-2,3 Dioxygenase

Abstract

Human mesenchymal stem cells (MSC) strongly repress activated T-cell proliferation through the production of a complex set of soluble factors, including the tryptophancatabolizing enzyme indoleamine 2,3-dioxygenase (IDO), which is induced by IFN-;. Conversely, MSCs support survival of follicular lymphoma (FL) B cells, in particular after exposure to tumor necrosis factor-A (TNF) and lymphotoxin-A1B2 (LT). The role of MSCs on normal and malignant B-cell growth in steady-state and inflammatory conditions remains to be fully explored. We show here that resting MSCs sustain activated normal B-cell proliferation and survival, whereas IFN-;-conditioned MSCs mediate IDOdependent B-cell growth arrest and apoptosis. IFN-;, TNF, and LT are significantly overexpressed by the microenvironment of invaded FL-lymph nodes, but their relative expression patterns are highly heterogeneous between samples. In vitro, IFN-; abrogates the B-cell supportive phenotype induced by TNF and LT on MSCs. Moreover, IFN-; overrules the growth promoting effect of MSCs on primary purified FL B cells. Altogether, these results underline the crucial role of the cytokine context in the local crosstalk between malignant cells and their microenvironment and provide new insights into our knowledge of the FL cell niche that emerges as a new promising target for innovative therapeutic strategies. [Cancer Res 2009;69(7):3228-37]

Monocytes and T cells cooperate to favor normal and follicular lymphoma B-cell growth: role of IL-15 and CD40L signaling

“…We thus decided to undertake CD40L-mediated proliferation assay as described above for normal B cells. Interestingly, we confirmed our previous study showing that a small but significant fraction of FL B cells were committed to cell division in response to CD40 triggering 21 and shown that IL-15 strengthened this effect (Figure 5c). In addition, purified FL B cells exhibited strong similarities with purified normal B cells including a lack of response to free IL-15 that could be restored after CD40L stimulation without any upregulation of the expression of IL-15Ra, IL-2Rb or IL-2Rg (Supplementary Figure S3).…”

“…Tonsil normal B cells and FL malignant B cells were purified as described. 21 CD10 pos GC B cells were further selected from purified normal B cells using PC5-conjugated anti-CD10 monoclonal antibody (mAb, Beckman Coulter, Villepinte, France) and a FACSAria cell sorter (Becton Dickinson, San Diego, CA, USA). Tonsil T cells were purified using the Pan T Cell isolation kit (Miltenyi Biotec, Bergisch Gladbach, Germany) and peripheral blood NK cells using the StemSep Human NK Cell Enrichment Kit (StemCell Technologies, Vancouver, Canada).…”

“…We planed next to address the role of endogeneous IL-15 in monocyte-driven B-cell survival. IL15 and IL15RA were targeted by a gene-silencing approach leading to a 53 ± 7% and 54 ± 10% decrease in the corresponding gene expression, respectively (Figure 1c 4,21 we also checked their capacity to trigger a functional IL-15-dependent signal. We previously demonstrated that tumor necrosis factor-a (TNF-a) and lymphotoxin-a1b2 (LT) reinforced the capacity of stromal cells to support B-cell survival.…”

“…Several factors could contribute to this induction. First, our previous study underlined an upregulation of IFNG in FL microenvironment, 21 and IFNg is an inducer of IL-15 in human monocytes. 28 Second, CD40L pos T cells are one of the main non-malignant cell partners for FL B cells, and CD40 triggering increases IL-15Ra expression on myeloid cells.…”

MicroRNA‐181a Regulates Local Immune Balance by Inhibiting Proliferation and Immunosuppressive Properties of Mesenchymal Stem Cells

“…Previous reports showed that human MSCs do not constitutively express IDO, but that IDO protein expression is induced by treatment with interferon (IFN)-c [34]. Moreover, IFN-c treatment of MSCs stimulates IDO enzyme activity in a dose-dependent manner.…”