Effect of the tyrosine kinase inhibitor dasatinib on lymphocyte trafficking

Resumen

Dasatinib is a tyrosine kinase inhibitor (TKI) of the oncogenic fusion protein BCR-ABL1 approved for Philadelphia chromosome (Ph+) chronic myeloid leukemia (CML) and acute lymphoblastic leukemia (ALL). Furthermore, mantle cell lymphoma (MCL) is an aggressive lymphoma with few curative options, although other TKIs have induced a certain therapeutic response. Therefore, we have explored dasatinib as a therapeutic option for MCL. However, in vitro evaluation of the direct effect of dasatinib on adhesion and migration using MCL cells did not render promising results. While very effective and well tolerated, dasatinib-treated patients often exhibit a transient lymphocytosis that peaks 2 hours after the intake of the drug and resolves spontaneously 4 hours later. Although it has been associated with better response to treatment, the cause underlying this lymphocytosis is currently unknown. Given its potential therapeutic benefits, identifying the mechanism by which dasatinib causes lymphocytosis is of clinical interest. To this end, we performed in vitro assays which suggested a dasatinib-induced defect on the adhesion of human healthy lymphocytes to endothelial cells and on the migration of B cells. Similarly, dasatinib caused a strong decrease in murine B cell in vitro chemotaxis towards the homeostatic chemokines CCL21, CXCL12 and CXCL13, constitutively expressed in secondary lymphoid organs (SLOs), while T cell chemotaxis remained unaffected. However, our in vitro results did not translate into a defective homing in our mouse model of dasatinib induced lymphocytosis. In contrast, dasatinib caused a significant shrinkage of spleen size, which correlated with increased lymphocyte egress from SLO. After discarding an effect on S1P/S1PR1 axis, which has an essential role on lymphocyte egress, we hypothesized that dasatinib might affect non-hematopoietic cells, causing disturbed lymphocyte trafficking. In particular, we focused on contractile fibroblastic reticular cells (FRCs), which play an important role in the maintenance of lymphoid organ size and structure of SLOs. Pharmacological inhibition of the contraction-promoting factor ROCK partially reversed dasatinib-induced lymphocytosis and egress in vivo. In vitro, dasatinib partially counteracted the strong effect of ROCK inhibition on FRCs actin dynamics. Furthermore, intravital imaging of lymphoid tissue uncovered a strong decrease in both B and T cell motility after dasatinib administration. Finally, preliminary data from a current study confirm that spleen volume reduction also occurs in dasatinib-treated CML patients, concomitant to lymphocytosis. In summary, these observations suggest that alterations of the microenvironment of SLO, in particular on lymphoid tissue stromal cells, can interfere with lymphocyte migration, providing a mechanism to explain dasatinib-induced lymphocytosis.