title: 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 tryptophan-catabolizing enzyme indoleamine 2,3-dioxygenase (IDO), which is induced by IFN-gamma. Conversely, MSCs support survival of follicular lymphoma (FL) B cells, in particular after exposure to tumor necrosis factor-alpha (TNF) and lymphotoxin-alpha1beta2 (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-gamma-conditioned MSCs mediate IDO-dependent B-cell growth arrest and apoptosis. IFN-gamma, 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-gamma abrogates the B-cell supportive phenotype induced by TNF and LT on MSCs. Moreover, IFN-gamma 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.
authors.affiliation: Institut National de la Sante et de la Recherche Medicale U917, IFR140, Université Rennes 1, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Maby-El Hajjami
authors.forename: Patricia
authors.initials: P
authors.lastname: Amé-Thomas
authors.forename: Céline
authors.initials: C
authors.lastname: Pangault
authors.forename: Olivier
authors.initials: O
authors.lastname: Tribut
authors.forename: John
authors.initials: J
authors.lastname: DeVos
authors.forename: Rachel
authors.initials: R
authors.lastname: Jean
authors.forename: Nadège
authors.initials: N
authors.lastname: Bescher
authors.forename: Céline
authors.initials: C
authors.lastname: Monvoisin
authors.forename: Joëlle
authors.initials: J
authors.lastname: Dulong
authors.forename: Thierry
authors.initials: T
authors.lastname: Lamy
authors.forename: Thierry
authors.initials: T
authors.lastname: Fest
authors.forename: Karin
authors.initials: K
authors.lastname: Tarte
mesh_terms: D001402:B-Lymphocytes / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D002470:Cell Survival / Q000276:immunology; D002648:Child; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000276:immunology*; D016898:Interferon-alpha / Q000276:immunology / Q000494:pharmacology; D007371:Interferon-gamma / Q000276:immunology / Q000494:pharmacology*; D008213:Lymphocyte Activation; D016393:Lymphoma, B-Cell / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D008224:Lymphoma, Follicular / Q000201:enzymology* / Q000276:immunology / Q000473:pathology*; D008648:Mesoderm / Q000201:enzymology* / Q000276:immunology / Q000473:pathology*; D017154:Stromal Cells / Q000201:enzymology / Q000276:immunology / Q000473:pathology
chemical_list: D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D016898:Interferon-alpha; D007371:Interferon-gamma