Stromal cell contribution to human follicular lymphoma pathogenesis

Abstract

Follicular lymphoma (FL) is the prototypical model of indolent B cell lymphoma displaying a strong dependence on a specialized cell microenvironment mimicking normal germinal center. Within malignant cell niches in invaded lymph nodes and bone marrow, external stimuli provided by infiltrating stromal cells make a pivotal contribution to disease development, progression, and drug resistance. The crosstalk between FL B cells and stromal cells is bidirectional, causing activation of both partners. In agreement, FL stromal cells exhibit specific phenotypic, transcriptomic, and functional properties. This review highlights the critical pathways involved in the direct tumor-promoting activity of stromal cells but also their role in the organization of FL cell niche through the recruitment of accessory immune cells and their polarization to a B cell supportive phenotype. Finally, deciphering the interplay between stromal cells and FL cells provides potential new therapeutic targets with the aim to mobilize malignant cells outside their protective microenvironment and increase their sensitivity to conventional treatment.

Keywords: B cells; bone marrow; cell interactions; lymph nodes; stromal cells.

Figure 1

Follicular lymphoma pathogenesis. The first step of follicular lymphoma (FL) development occurs in the bone marrow as a mistake in V(D)J rearrangement and leads to the ectopic expression of the antiapoptotic protein bcl2. After antigen encounter, naive B cells harboring the t(14;18) reach the germinal center where they display a selective growth advantage and could extensively recirculate as atypical IgM^pos low affinity memory B cells called follicular-lymphoma like cells (FLLC). Iterative reentries into germinal centers allow the acquisition of additional genetic alterations. The relationship between FLLC and FL is not formerly demonstrated but the hypothesis is that FLLC contain premalignant intermediates that could transform in some patients into FL. FL cells remain strongly dependent on bidirectional crosstalk with heterogeneous stromal cells, including activated fibroblastic reticular cells (FRC), altered follicular dendritic cells (FDC), and perhaps marginal reticular cells (MRC) of unknown origin and infiltrating immune cells including tumor-associated macrophages (TAM) and follicular helper T cells (T_FH). FL also developed in the bone marrow where B-cell clones could evolve independently within ectopic specific FL-supportive niches.

Figure 2

Follicular lymphoma cell niche. (A) Stromal cells recruit and support directly the growth of FL B cells through a combination of adhesion molecules, chemokines, and cytokines. Their supportive properties are strongly influenced by the local cytokine context, in particular by TNF-α and LT-α1β2 that are overexpressed by malignant B cells and promote lymphoid stromal cell differentiation. (B) FL-MSC overexpress the chemokine CCL2 that promotes monocyte recruitment and polarization into TAM-like cells. FL-TAM overexpress IL-15 that triggers, in cooperation with TFH-derived CD40L, STAT5-dependent FL B cell activation. (C) FL-TFH overexpress TNF-α and LT-α1β2, which favor stromal cell engagement into FRC differentiation, but also IL-4 that drive STAT6-dependent B-cell activation and contribute to the induction of TAM phenotype.