Abstract
Communication with the lymphoid microenvironment is essential for the survival and proliferation of neoplastic B cells in chronic lymphocytic leukemia (CLL). While nurse-like cells (NLCs) are recognized as key components of this niche, the mechanisms and functional impact of their interactions with malignant cells remain insufficiently understood. Here, using primary patient cells, we found that NLCs express high levels of folate receptor beta (FOLR2), which correlate with increased survival of leukemic cells in vitro. Unexpectedly, we found that CLL cells acquire functional FOLR2 from NLCs via trogocytosis, enhancing their folate uptake. To further study the biological relevance of this phenomenon, we modeled lymphoid microenvironmental activation using CD40L and IL-15, which markedly increased FOLR2 transfer and induced robust NLC-dependent CLL cell activation and proliferation. These processes were closely associated, as FOLR2+ CLL cells represented the predominant population of actively cycling leukemic cells. Under the same conditions, we also observed an additional contact-independent mechanism of FOLR2 transfer, suggesting involvement of extracellular vesicles (EVs). To validate these findings in situ, we performed multiplex immunofluorescence analysis of CLL lymph nodes. This confirmed the presence of FOLR2⁺ NLCs and demonstrated their significant enrichment in more aggressive and proliferative cases. In addition, we detected FOLR2+ CLL cells in situ, supporting the occurrence of trogocytosis and possibly EVs mediated-transfer in the lymphoid microenvironment. Together, these results identify FOLR2 as a novel marker of protective NLCs and implicate trogocytosis with NLCs as an important mechanism that enhances CLL cell adaptation and promotes leukemic cell activation and proliferation.