Mesenchymal stromal cells orchestrate follicular lymphoma cell niche through the CCL2-dependent recruitment and polarization of monocytes

Abstract

Accumulating evidence indicates that infiltrating stromal cells contribute directly and indirectly to tumor growth in a wide range of cancers. In follicular lymphoma (FL), malignant B cells are found admixed with heterogeneous lymphoid-like stro-mal cells within invaded lymph nodes and BM. In addition, mesenchymal stromal cells (MSCs) support in vitro FL B-cell survival, in particular after their engagement toward lymphoid differentiation. We show here that BM-MSCs obtained from patients with FL (FL-MSCs) display a specific gene expression profile compared with MSCs obtained from healthy age-matched donors (HD-MSCs). This FL-MSC signature is significantly enriched for genes associated with a lymphoid-like commitment. Interestingly, CCL2 could be detected at a high level within the FL-cell niche, is up-regulated in HD-MSCs by coculture with malignant B cells, and is overexpressed by FL-MSCs, in agreement with their capacity to recruit mono-cytes more efficiently than HD-MSCs. Moreover, FL-MSCs and macrophages cooperate to sustain malignant B-cell growth, whereas FL-MSCs drive monocyte differentiation toward a proangiogenic and lipopolysaccharide-unresponsive phenotype close to that of tumor-associated mac-rophages. Altogether, these results highlight the complex role of FL stromal cells that promote direct tumor B-cell growth and orchestrate FL-cell niche, thus emerging as a potential therapeutic target in this disease. (Blood. 2012;119(11):2556-2567)

Pathogenesis of follicular lymphoma

“…FTH cells are enriched in FL biopsies and secrete cytokines such as IL-4, which binds to the IL-4 receptor on lymphoma cells and triggers signaling by phosphorylation of ERK and STAT6 (78). The role of stromal cells in FL pathogenesis has emerged, as in vitro studies have shown that they increase neoplastic B cell survival, contribute to monocyte recruitment via the secretion of CCL2, and contribute to macrophage polarization (79,80).…”

Follicular Lymphoma: The Role of the Tumor Microenvironment in Prognosis

“…1) and triggers signaling by phosphorylation of extracellular signal-regulated kinase and STAT6. 57 The role of stromal cells in FL pathogenesis has begun to emerge; in vitro studies have shown that stromal cells increase neoplastic B-cell survival, contribute to monocyte recruitment via the secretion of CCL2 58,59 (left lower side of the orange open circle of "follicular reticular cell FRC" cell in Fig.1), and contribute to macrophage polarization (the blue open circle of "M2 LAM" on the left lower corner in Fig.1). Data from co-culture experiments with bone marrow-derived mesenchymal stromal cells suggest that the malignant cells induce changes in stromal cells toward lymphoid differentiation and overexpression of CCL2, which in turn leads to the recruitment of monocytes that are differentiated into a TAM phenotype.…”

“…Data from co-culture experiments with bone marrow-derived mesenchymal stromal cells suggest that the malignant cells induce changes in stromal cells toward lymphoid differentiation and overexpression of CCL2, which in turn leads to the recruitment of monocytes that are differentiated into a TAM phenotype. 59 The localization of CD4 + T cells within neoplastic follicles, unlike their absolute number, was associated with poor survival and rapid transformation. TFH provide survival signals to antigen-selected GC B cells, and help them achieve class-switch recombination and differentiation into antibodysecreting plasma cells.…”

Tumor-associated macrophages in diffuse large B-cell lymphoma

“…In follicular lymphoma, stromal cells derived from mononucleated cells have been shown in vitro to secrete CCL2, thereby recruiting monocytes and differentiating them into a tumor-promoting phenotype. 23 A similar insight into macrophage biology is currently lacking in DLBCL. Another question of interest is whether the observed outcome correlations will hold true for other anti-CD20 antibodies and whether the principle of increased antibody-dependent cellular cytotoxicity/phagocytosis of opsonized tumor cells in the presence of macrophages can be generalized to all malignancies that are amenable to monoclonal antibody-based therapy.…”