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Review
. 2023 Nov 2:14:1288110.
doi: 10.3389/fimmu.2023.1288110. eCollection 2023.

Modeling the crosstalk between malignant B cells and their microenvironment in B-cell lymphomas: challenges and opportunities

Baptiste Brauge  1 , Elise Dessauge  1 , Florent Creusat  1 , Karin Tarte  1   2
Affiliations
Review

Modeling the crosstalk between malignant B cells and their microenvironment in B-cell lymphomas: challenges and opportunities

Baptiste Brauge et al. Front Immunol. .

Abstract

B-cell lymphomas are a group of heterogeneous neoplasms resulting from the clonal expansion of mature B cells arrested at various stages of differentiation. Specifically, two lymphoma subtypes arise from germinal centers (GCs), namely follicular lymphoma (FL) and GC B-cell diffuse large B-cell lymphoma (GCB-DLBCL). In addition to recent advances in describing the genetic landscape of FL and GCB-DLBCL, tumor microenvironment (TME) has progressively emerged as a central determinant of early lymphomagenesis, subclonal evolution, and late progression/transformation. The lymphoma-supportive niche integrates a dynamic and coordinated network of immune and stromal cells defining microarchitecture and mechanical constraints and regulating tumor cell migration, survival, proliferation, and immune escape. Several questions are still unsolved regarding the interplay between lymphoma B cells and their TME, including the mechanisms supporting these bidirectional interactions, the impact of the kinetic and spatial heterogeneity of the tumor niche on B-cell heterogeneity, and how individual genetic alterations can trigger both B-cell intrinsic and B-cell extrinsic signals driving the reprogramming of non-malignant cells. Finally, it is not clear whether these interactions might promote resistance to treatment or, conversely, offer valuable therapeutic opportunities. A major challenge in addressing these questions is the lack of relevant models integrating tumor cells with specific genetic hits, non-malignant cells with adequate functional properties and organization, extracellular matrix, and biomechanical forces. We propose here an overview of the 3D in vitro models, xenograft approaches, and genetically-engineered mouse models recently developed to study GC B-cell lymphomas with a specific focus on the pros and cons of each strategy in understanding B-cell lymphomagenesis and evaluating new therapeutic strategies.

Keywords: 3D models; diffuse large B-cell lymphoma; follicular lymphoma; genetically-engineered mouse models; germinal center; stromal cells; tumor microenvironment; xenografts.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
In vivo models of B-cell lymphoma transplantation. In syngenic models, murine cells are derived from immortalized mouse lymphoma cells from the same inbred strain as the immunocompetent recipient mice and are implanted by intravenous (iv) or subcutaneous (sc) injection. Xenogeneic models are based on human lymphoma cell line (cell-line derived xenograft) or primary lymphoma cells (patient-derived xenograft) grafted in immunocompromised or humanized mice.
Figure 2
Figure 2
Strategies to study the effect of genetic alterations on GC biology and lymphomagenesis. In chimeric mouse models, hematopoietic stem and progenitor cells (HSPCs) are harvested from WT (A) or BCL2-deregulated (B) mouse and transduced with a vector driving the silencing (shRNA), or the overexpression (WT or mutated gene) of the gene of interest. Transduced cells are then used to reconstitute WT mouse BM. In transgenic mouse models, a CRE recombinase under the dependence of a promoter deregulating the gene of interest at a specific stage of B-cell differentiation is associated with a floxed gene of interest (C). These models can be crossed with BCL2-deregulated mouse models (D). The different tools to deregulate BCL2 are indicated in the yellow box.
Figure 3
Figure 3
Impact of FL recurrent genetic hits on the crosstalk between B cells and their TME as revealed in GEMM. Crebbp LOF is associated to a loss of MHC class II expression preventing antigen presentation to CD4pos T cells as well as a decreased infiltration of CD4pos and CD8pos T cells within TME. When combined with Kmt2d loss-of-function, Crebbp alteration leads to an exclusion of CD8pos T cells from GCs. Hvem loss-of-function triggers over-activation of Tfh, FDC, and FRC, and upregulates BCR signaling. Ezh2 gain-of-function mutations skew the Tfh dependence of tumor B cells towards FDC, in part because such mutations yield CD40, MHC-I, and MHC-II downregulation, and leads to CD58 silencing. Ctss GOF mutations favor an increase in Tfh infiltration and MHC-II presentation, while preventing CD8pos T cells to infiltrate the tumors. Rragc activating mutations lead to resistance to nutrient withdrawal and decrease the need for Tfh support. Finally, loss-of-function of the confinement receptors Gna13 or S1pr2 is associated with B-cell dissemination outside GC and LN. The main remaining questions in the field are indicated. Generated with Biorender.
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Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. BB is a recipient of a fellowship from the Rennes University, the Région Bretagne, and the Ligue Nationale contre le Cancer. This work is supported by the Ligue Nationale contre le Cancer (Equipe Labellisée), and the Institut National du cancer (INCA AAP PNP-19-009 and TRANSCAN-3 BIALYMP program).