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

¹ Institut National de la Sante et de la Recherche Medicale U917, IFR140, Université Rennes 1, France; ² Pôle Cellules et Tissus, ³ Laboratoire de Pharmacologie, and ⁴ Service d'Hématologie Clinique, CHU Rennes, France; ⁵ Institut National de la Sante et de la Recherche Medicale U847, CHU Montpellier, France; and ⁶ EFS Bretagne, Rennes, France

Requests for reprints: Karin Tarte, Institut National de la Sante et de la Recherche Medicale U917, Faculté de médecine - 2 Avenue du Pr Léon Bernard, 35043 RENNES - France. Phone: 33-2-23-23-4512; Fax: 33-2-23-23-4958; E-mail: karin.tarte{at}univ-rennes1.fr.

Key Words: mesenchymal stem cells • lymphoma • indoleamine- 2,3 dioxygenase

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-. Conversely, MSCs support survival of follicular lymphoma (FL) B cells, in particular after exposure to tumor necrosis factor- (TNF) and lymphotoxin-1β2 (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 IDO–dependent 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]