The Source of the Stroma Affects the Trafficking Potential of Mantle Lymphoma Cells and Alters the Effect of Ibrutinib on Their Survival

Introduction: Mantle cell lymphoma (MCL) is characterized by dissemination of malignant B-lymphocytes in different compartments, mainly lymph-nodes (LN) and bone-marrow (BM). The interaction between lymphoma cells and their microenvironment is mediated by adhesion molecules and signaling cues regulating malignant cell behavior. This study is aimed to explore the relations between MCL cells and different stromal cells, comparing their effects on lymphoma cell trafficking and response to ibrutinib, a Bruton`s tyrosine kinase inhibitor.

Results: Co-culture of MCL cells with BM- and LN-derived stromal cells increased the expression of CD44 and CXCR4. Ibrutinib treatment resulted in robust apoptosis of lymphoma cells. However, co-culture with stromal cells demonstrated an apoptosis-protection effect, where BM stromal cells showed higher effect than LN. Ibrutinib-resistance was also demonstrated under non-contact conditions, suggesting that secreted factors are involved.

Stromal barrier increased the migration potential of MCL through BM stroma and LN cells compared to non-adherent conditions. Ibrutinib decreased cell migration through BM stromal cells; however, resulted in opposite effect when cells encountered LN stromal cells. Moreover, conditioned medium obtained from LN stroma facilitated extensive lymphoma cell migration that was impaired following AMD3100 treatment. In contrast, BM-derived stromal conditioned medium barely promoted lymphoma cell migration with no effect of AMD3100 treatment.

Conclusions: Our results point to substantial differences in lymphoma behavior and ibrutinib response depending on stromal cell source. These differences may be mediated by the unique adhesion interaction and specific survival signals provided by each stromal source. The different adhesion constellation and modulations in the lymphoma environment had a diverse effect on Ibrutinib outcome. Therefore, in MCL patients overall response to therapy may be determined by lymphoma dissemination patterns and organ involvement.