Abstract
The biology of follicular lymphoma (FL) is largely dictated by the immune-effector and stromal cells that comprise its tumor microenvironment. FL-infiltrating T-cell populations that are thought to be fundamental to FL biology are follicular helper T-cells (TFH), follicular regulatory T-cells (TFR), a recently described population that regulates TFH activity, and regulatory T-cells (Treg). These T-cell populations have dynamic interactions with mesenchymal stromal cells (MSCs) in the tumor microenvironment. Whereas MSCs have been shown to support FL B-cell and Treg viability, their effects on FL-infiltrating TFH and TFR cells have not been described. Herein we show that MSCs support the viability of FL-infiltrating TFH and TFR, as well as Tregs, in part through an IL-6-dependent mechanism. We further demonstrate that MSCs mediate TFH to TFR conversion by inducing the expression of FoxP3 in TFH cells, demonstrating for the first time that human TFR can be derived from TFH cells. Given that the balance of TFH and TFR populations likely dictate, in part, the biology of this disease, our data support the potential for targeting MSCs as a therapeutic strategy.
Highlights
Follicular lymphoma (FL) is an indolent lymphoma having a natural history, which is dictated, in part, by the interactions between the malignant B-cells and the non-malignant cells comprising its microenvironment
We demonstrate that: a) Mesenchymal Stromal Cells (MSCs) support the viability of FL-infiltrating TFH and T-follicular regulatory cells (TFR) in part, through an IL-6-dependent mechanism and b) MSCs promote the differentiation of TFH to TFR by inducing their expression of FoxP3
Characterization of Lymphoid-derived Stromal Cells MSCs isolated from healthy donor tonsils (TN) and FL-involved tissues displayed typical fibroblast morphology and expressed surface proteins characteristic of MSCs (CD73, CD90, CD105, CD106 and fibroblast activation protein (FAP)), while lacking expression of the lineage specific markers CD14, CD34, CD45 and HLA-DR (Fig. S1A)
Summary
Follicular lymphoma (FL) is an indolent lymphoma having a natural history, which is dictated, in part, by the interactions between the malignant B-cells and the non-malignant cells comprising its microenvironment One component of this microenvironment, which has been shown to support the viability and induce the chemotherapeutic resistance of FL B-cells, are Mesenchymal Stromal Cells (MSCs) [1,2]. Gene expression and immunohistochemistry studies demonstrate that FL-infiltrating Th cells impact FL biology and show a correlation between the number and anatomical location of distinct Th cell populations with patient survival [7] One such Th cell population is regulatory T-cells (Treg), a T-cell subset which suppresses both effector T-cell priming and cytotoxicity and whose differentiation is controlled by the FoxP3 transcription factor. MSCs have been shown to induce the differentiation of naıve T-cells to Tregs, and as such MSCs may modulate FL biology, in part, through their support of Treg differentiation [9]
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