Presentation of HONEYCOMB

B-cell expansion, differentiation, and selection within secondary lymphoid organs (SLO) rely on a complex network of cell interactions finely regulated in their kinetic and localization and whose deregulation creates a propitious environment for B-cell dysimmune diseases and oncogenesis. In particular Follicular Lymphoma (FL) and Diffuse large B-cell lymphomas (DLBCL), the two most common B-cell Non-Hodgkin's Lymphomas (B-NHL), are both derived from germinal center (GC) B cells but are characterized by opposite patterns of tumor niche composition and organization, making them interesting models to understand how these two parameters could influence lymphomagenesis dynamics.

In the past 5 years, we have in particular focused on FL as a paradigm of B-cell malignancy dependent on a permissive microenvironment within invaded lymph nodes (LN) and bone marrow (BM). We have provided new insights on how FL-infiltrating Tfh, stromal cells, and myeloid cells could seed lymphomagenesis and how tumor B-cell features favor in turn the selection of a specific supportive microenvironment.

We now further develop strategies to analyze, at the single-cell level, cell heterogeneity and differentiation trajectories of myeloid and stromal cells with the setup of new relevant mouse models (genetically engineered and xenograft) and 3D alginate spheroid models to address the functional heterogeneity of B-cell niche in normal tissue and B-cell lymphomas. As a complementary model, early B-cell BM stromal niche is investigated with similar tools in a new research axis. We also open a new project dedicated to autoimmune diseases as models of non-malignant pathogenic activation of lymphoid tissues.

Importantly, our team is organized as a continuum from bedside to bench with a strong commitment to translate our findings to patient care and to take opportunity of clinical observations/trials to feed our research programs.

• Project 1. Functional heterogeneity of human stromal cells: from basic science to clinical applications
• Project 2. Functional heterogeneity of follicular lymphoma tumor microenvironment
• Project 3. Stromal cell commitment and epigenetics
• Project 4. Tackling BM supportive niches in B-cell acute leukemia
• Project 5. Heterogeneity and commitment of suppressive myeloid cells

1. New insights into the functional heterogeneity of Follicular Lymphoma (FL) supportive microenvironment, including Tfh (Ame-Thomas, Blood 2015) and stromal cells (Pandey, Blood 2017), and demonstration that FL genetics directly impact the capacity of tumor cells to interact with (Amin, Blood 2015) and to instruct (Boice, Salloum, Mourcin, Cell 2016) tumor microenvironment.
2. Identification of the heterogeneity (Uhel, JACI 2019; Roussel, Methods Mol Biol 2019; Roussel, Cancer Immunol Immunother 2017; Roussel, Cancer Immunol Immunother 2020) and specific roles of myeloid cells as direct (Amin, Blood 2015) and indirect (Azzaoui, Blood 2016; Gregoire, Oncotarget 2015) lymphoma-promoting compartment
3. Identification of myeloid cells as key players of immune dysfunctions in acute inflammation (Gaudriot, Shock 2015; Gregoire, J Leukoc Biol 2017; Uhel, AJRCCM 2017; Gregoire, Eur Resp J 2018).
4. Deciphering the clinical impact of mesenchymal stromal cell heterogeneity for cell therapy approaches (Loisel, Stem Cells 2017; Ménard, Stem Cells 2020).
5. Development of new tools to analyze the dynamic of stromal cell/tumor cell crosstalk in 3D in vitro models (Patent PCT/FR2018/050855) and in original triple transgenic conditional mouse models in collaboration with Team 3 (AIDCreER+/- Hvemf/f R26Tomato+/+ 3'RRhuBcl2 and AIDCreER+/- Kmt2df/f R26Tomato+/+ 3'RRhuBcl2)