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

• Published in: Cancer research (Chicago, Ill.) Ill.), 2009-04, Vol.69 (7), p.3228-3237
• Main Authors: MABY-EL HAJJAMI, Hélène, AME-THOMAS, Patricia, FEST, Thierry, TARTE, Karin, PANGAULT, Céline, TRIBUT, Olivier, DEVOS, John, JEAN, Rachel, BESCHER, Nadège, MONVOISIN, Céline, DULONG, Joëlle, LAMY, Thierry
• Format: Article
• Language: English
• Subjects: Antineoplastic agents; B-Lymphocytes; B-Lymphocytes - enzymology; B-Lymphocytes - immunology; B-Lymphocytes - pathology; Biological and medical sciences; Cancer; Cell Survival; Cell Survival - immunology; Child; Hematologic and hematopoietic diseases; Humans; Indoleamine-Pyrrole 2,3,-Dioxygenase; Indoleamine-Pyrrole 2,3,-Dioxygenase - immunology; Interferon-alpha; Interferon-alpha - immunology; Interferon-alpha - pharmacology; Interferon-gamma; Interferon-gamma - immunology; Interferon-gamma - pharmacology; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Life Sciences; Lymphocyte Activation; Lymphoma, B-Cell; Lymphoma, B-Cell - enzymology; Lymphoma, B-Cell - immunology; Lymphoma, B-Cell - pathology; Lymphoma, Follicular; Lymphoma, Follicular - enzymology; Lymphoma, Follicular - immunology; Lymphoma, Follicular - pathology; Medical sciences; Mesoderm; Mesoderm - enzymology; Mesoderm - immunology; Mesoderm - pathology; Pharmacology. Drug treatments; Stromal Cells; Stromal Cells - enzymology; Stromal Cells - immunology; Stromal Cells - pathology; Tumors
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-08-3000

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.