Pré-Publication, Document De Travail Année : 2025

FOLR2 transfer by trogocytosis from nurse-like cells to CLL cells is linked to their activation and proliferation

Résumé

ABSTRACT Neoplastic B cells in chronic lymphocytic leukemia (CLL) are particularly dependent on the tumor microenvironment (TME) located in lymphoid organs. Contact with microenvironment facilitates survival, proliferation and resistance to treatment of CLL cells. Here, we studied the interaction between CLL cells and nurse-like cells (NLCs), a subtype of macrophages heavily implicated in the pathogenesis of this disease. Using in vitro cultures of human primary cells, we demonstrated that NLCs express high levels of folate receptor beta (FOLR2), which correlates with survival of CLL cells. Next, we discovered that CLL cells acquire functional FOLR2 from the NLCs through trogocytosis, thereby increasing their uptake of folates. Treatment of CLL and NLC co-cultures with IL-15 and CD40L, to mimic TME, substantially increases the frequency of FOLR2⁺ CLL cells, which are significantly enriched in activated and proliferating fraction of the cells, particularly under folic acid depletion. With multi-immunofluorescence analysis of CLL patients’ lymph nodes, we confirmed the presence of FOLR2⁺ NLCs, whose frequency correlates with increased proliferation of cancer cells. Further detection of FOLR2⁺ CLL cells, provided evidence of trogocytosis in vivo. Finally, based on CD163/FOLR2 co-staining and spatial distribution of NLCs we uncovered heterogenous subpopulations of these cells suggesting their various specialization. This work proposes trogocytosis as an important mechanism of NLC-dependent support of CLL cells, and underscore FOLR2 as a new marker of NLCs. It paves a way to further study the impact of trogocytosis on progression of CLL and beyond. Scheme 1 Schematic representation of trogocytosis-mediated acquisition of NLC-derived FOLR2 by CLL cells promotes cancer cells adaptability and proliferation. 1) CLL cells enter the lymph node (LN) and engage in contact with FOLR2 + NLCs. 2) The presence of T cell- and stromal cell-derived cytokines, CD40L and IL-15 promotes the activation and trogocytosis-mediated acquisition of FOLR2 by CLL cells. 3) FOLR2⁺ trogocytic CLL cells have an advantage in folate acquisition and show increased proliferation compared to the remaining population of cancer cells. SUMMARY FOLR2 is a marker of M2-like protective NLCs CLL cells acquire functional FOLR2 from NLCs through trogocytosis, allowing them to enhance folate uptake Trogocytic FOLR2 + CLL cells are enriched in the fraction of activated and proliferative cells, especially during folic acid scarcity Discovery of FOLR2 + NLCs and FOLR2 + trogocytic CLL cells in the LNs of CLL patients.

Dates et versions

hal-05263935 , version 1 (16-09-2025)

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Marcin Domagala, Chloe Bazile, Bastien Gerby, Loïc Ysebaert, Vera Pancaldi, et al.. FOLR2 transfer by trogocytosis from nurse-like cells to CLL cells is linked to their activation and proliferation. 2025. ⟨hal-05263935⟩
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