We characterized the molecular crosstalks responsible for a protective microenvironment and the formation of a tumor cell niche.

B cells from CLL or MCL infiltrate stromal cell lines or bone marrow-derived stromal cells in ex-vivo cultures, enhancing tumor survival. This protective role of the stromal layer is mediated by the stabilization of BCR signaling effectors in malignant B cells. In particular, we have demonstrated a dual role of stabilized b-catenin, at the plasma membrane by promoting adhesion to stromal cells and in the nucleus by inducing transcription of pro-survival factors such as IL6. Also, tumor cells promote metabolic changes in stromal cells, which in turn produce factors (Wnt16) that further activate B cells (G Lazarian et al., Oncogene 2020).

Our cartography of CLL lymph node biopsies confirmed the tumor-induced alteration of the microenvironment. Follicular dendritic cells are no longer observed and residual follicular reticular cells are organized in pseudo-follicles. Lymph nodes are extensively infiltrated by tumor B cells and monocyte-derived cells with tumor-associated macrophages markers (M2). The latter are an alternative source of CCL21 which serve to anchor CCR7+-CLL B cells. Besides these infiltrates in lymphoid sanctuary organs, our systemic analysis showed a striking differential propensity of patients’ peripheral blood mononuclear cells to differentiate into M2-Nurse Like Cells (NLC) during cell culture. At the molecular level, differentiated NLCs secrete chemokines (CXCL12 and CXCL13) responsible for B cell motility and produce CCL21, which is retained at the membrane and capture CCR7-expressing CLL B cells (R Zabboub et al. Blood Advances 2022).