Follicular lymphoma (FL) results from the malignant transformation of germinal center B cells and is characterized by recurrent genetic alterations providing a direct growth advantage and/or facilitating interaction with tumor microenvironment. In agreement, accumulating evidences suggest a dynamic bidirectional crosstalk between FL B cells and surrounding non-malignant cells that coevolve within specialized niches in invaded lymph nodes (LN) and bone marrow (BM).
FL cancer-associated fibroblasts (FL-CAF) have progressively emerged as major organizers of FL niches. We initially demonstrated that FL-CAF overexpress CCL2 and IL-8, involved in the recruitment of monocytes and neutrophils, and convert recruited monocytes into proangiogenic and anti-inflammatory TAM-like cells, whereas they protect recruited neutrophils from apoptosis. Similarly, FL-CAF could contribute to the overexpression of IL-4 by FL-Tfh and conversely, Tfh-derived IL-4 triggers CXCL12 overexpression in FL-CAF, resulting in FL B cell recruitment and activation. In order to further delineate the properties of FL-CAFs in situ we recently analyzed the gene expression profile of sorted follicular dendritic cells (FDC), fibroblastic reticular cells (FRC), and their putative local precursors in FL LN and reactive secondary lymphoid organs. Interactome analysis demonstrated that FL B cells had a higher capacity to interact with FRC than with FDC, providing a molecular support for the disruption of the FDC network within FL follicles. Moreover, we confirmed the deregulation of CXCL12 and highlighted an overexpression of CCL19/CCL21 by FL-CAF. In turn TNF/LT and TGFb, both overexpress by FL B cells, synergize to induce FL-CAF markers, including CXCL12, CCL19, and CCL2, on LN stromal cells. Moreover, we could demonstrate a correlation between TGFB1 and CCL21 expression across large series of FL patients. As a disseminated disease, spatial heterogeneity is another level of heterogeneity in FL, with a specific emphasis on BM versus LN niches. Importantly, we demonstrate that stromal cells from non-invaded FL BM already display some phenotypic and transcriptomic alterations. This discrepancy has been recently solved by the demonstration that FL B cells produce extracellular vesicles that could be internalized by distant BM stromal cells, making them more efficient to support BM FL B-cell survival and quiescence, at least in part through the production of CXCL12.
Even if several questions remain open, concerning FL-CAF origin, differentiation pathways, and heterogeneity, they progressively emerge as key drivers of FL pathogenesis and relevant therapeutic targets in this still fatal malignancy.