Intratumoral immune and stromal heterogeneity in follicular lymphoma: an implication in relapses and responses to immunotherapies?

International audienc

Lymphoid-like extracellular matrix partially polarizes stroma cells toward a lymphoid phenotype

International audienc

Loss of the HVEM Tumor Suppressor in Lymphoma and Restoration by Modified CAR-T Cells.

The HVEM (TNFRSF14) receptor gene is among the most frequently mutated genes in germinal center lymphomas. We report that loss of HVEM leads to cell-autonomous activation of B cell proliferation and drives the development of GC lymphomas in vivo. HVEM-deficient lymphoma B cells also induce a tumor-supportive microenvironment marked by exacerbated lymphoid stroma activation and increased recruitment of T follicular helper (TFH) cells. These changes result from the disruption of inhibitory cell-cell interactions between the HVEM and BTLA (B and T lymphocyte attenuator) receptors. Accordingly, administration of the HVEM ectodomain protein (solHVEM((P37-V202))) binds BTLA and restores tumor suppression. To deliver solHVEM to lymphomas in vivo, we engineered CD19-targeted chimeric antigen receptor (CAR) T cells that produce solHVEM locally and continuously. These modified CAR-T cells show enhanced therapeutic activity against xenografted lymphomas. Hence, the HVEM-BTLA axis opposes lymphoma development, and our study illustrates the use of CAR-T cells as "micro-pharmacies" able to deliver an anti-cancer protein

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

International audienceStromal 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