LAUSR

Tumor microenvironment exerts critical roles in sustaining homing, retention and survival of chronic lymphocytic leukemia (CLL) cells in secondary lymphoid organs. Such conditions foster immune surveillance escape as well as resistance to current therapies. The physiological microenvironment is rendered tumor permissive by a complex interplay of chemokines, chemokine receptors and adhesion molecules, as well as by direct interactions between the malignant lymphocytes and stromal cells, T-cells and specialized macrophages referred to as nurse like cells (NLCs). In order to characterize this complex interplay, we investigated the altered architecture on CLL lymph nodes biopsies and observed by immunohistochemistry and immunofluorescence a dramatic loss of tissue sub-compartments and stromal cell networks as compared with non-malignant lymph nodes. A supplemental high density of CD68+ cells expressing the homeostatic chemokine CCL21 was randomly distributed. Using an imaging flow cytometry approach, CCL21 mRNA and the corresponding protein were observed in single CD68+ NLCs differentiated in vitro from CLL PBMCs. The chemokine was sequestered at the NLC membrane helping the capture of CCR7-high expressing CLL B cells. Inhibiting the CCL21/CCR7 interaction by blocking antibodies or using therapeutic Ibrutinib altered the adhesion of leukemic cells. Our results indicate NLCs as providers of an alternative source of CCL21, taking over the physiological task of follicular reticular cells (FRCs) whose network is deeply altered in CLL lymph nodes. Moreover, CCL21, by retaining malignant B cells, provide a protective environment for their niching and survival thus allowing immune tumor survey evasion and resistance to treatment. These findings argue for a specific targeting or re-education of NLCs as a new immunotherapy strategy for this still deadly disease.