B cell/stromal cell crosstalk in health, disease, and treatment: Follicular lymphoma as a paradigm

Abstract

Stromal cells organize specific anatomic compartments within bone marrow (BM) and secondary lymphoid organs where they finely regulate the behavior of mature normal B cells. In particular, lymphoid stromal cells (LSCs) form a phenotypically heterogeneous compartment including various cell subsets variably supporting B-cell survival, activation, proliferation, and differentiation. In turn, activated B cells trigger in-depth remodeling of LSC networks within lymph nodes (LN) and BM. Follicular lymphoma (FL) is one of the best paradigms of a B-cell neoplasia depending on a specific tumor microenvironment (TME), including cancer-associated fibroblasts (CAFs) emerging from the reprogramming of LN LSCs or poorly characterized local BM precursors. FL-CAFs support directly malignant B-cell growth and orchestrate FL permissive cell niche by contributing, through a bidirectional crosstalk, to the recruitment and polarization of immune TME subsets. Recent studies have highlighted a previously unexpected level of heterogeneity of both FL B cells and FL TME, underlined by FL-CAF plasticity. A better understanding of the signaling pathways, molecular mechanisms, and kinetic of stromal cell remodeling in FL would be useful to delineate new predictive markers and new therapeutic approaches in this still fatal malignancy. K E Y W O R D S cancer-associated fibroblasts, cell plasticity, fibroblastic reticular cells, follicular dendritic cells, lymphoma, tumor microenvironment This article is part of a series of reviews covering Immunological functions of fibroblasts in human health and disease appearing in Volume 302 of Immunological Reviews. How to cite this article: Lamaison C, Tarte K. B cell/stromal cell crosstalk in health, disease, and treatment: Follicular lymphoma as a paradigm.

Advances in the multi-omics landscape of follicular lymphoma

“…The TME consists of T cells, macrophages, stromal cells, and a smaller proportion of neutrophils and natural killer (NK) cells [8,[77][78][79]. Recently, single-cell RNA sequencing, mass cytometry by time of flight (CyTOF) and reverse phase protein array (RPPA) studies provide a comprehensive picture of microenvironmental cell components at the transcriptomics and proteomics levels [69,71,72].…”

Bone Marrow Lymphoid Niche Adaptation to Mature B Cell Neoplasms

“…DLBCL show a mixed pattern of BM involvement that can potentially range from localized focal infiltrates to complete disruption of BM by lymphoma cell proliferation ( 37 ). In contrast, FL infiltration is primarily localized to the paratrabecular regions as nodular aggregates admixed with lymphoid-like TME ( 38 ). In CLL several BM infiltration patterns can be found including mixed nodular-interstitial, interstitial, and diffuse ( 39 ).…”

“…The protumoral role of infiltrating lymphoid stromal cells has been demonstrated in particular by the identification of ectopically-induced FRC- and FDC-like cells within invaded BM ( 40 , 70 ). To date the origin and heterogeneity of the stromal cells supporting FL B cells within LN and BM are not perfectly understood and it is very likely that several FL CAF subtypes co-exist and organize different cell niches with specific functions ( 38 ). Stromal cells supporting FL B cell survival have been initially identified as lymphoid-like stromal cells obtained in vitro by stimulation of BM mesenchymal precursors by TNF-α (TNF) and Lymphotoxin-α1β2 (LT) or by direct contact with malignant B cells ( 3 ).…”

Tumor Microenvironment and Microvascular Density in Follicular Lymphoma

“…FL results from the clonal expansion of germinal center (GC) B cells, even if malignant transformation is initiated during early B-cell development in the bone marrow, by aberrant repair failure of V(D)J recombination. The resulting t(14;18) translocation promotes high expression of the anti-apoptotic protein BCL2 [ 4 ], providing a survival advantage to B cells during GC reaction, wherein BCL2 is normally actively repressed by the GC-specific transcriptional machinery [ 5 , 6 ].…”