Enhanced Chemokine Receptor Recycling and Impaired S1P1 Expression Promote Leukemic Cell Infiltration of Lymph Nodes in Chronic Lymphocytic Leukemia

Abstract

Lymphocyte trafficking is orchestrated by chemokine and sphingosine 1-phosphate (S1P) receptors that enable homing and egress from secondary lymphoid organs (SLO). These receptors undergo rapid internalization and plasma membrane recycling to calibrate cellular responses to local chemoattractants. Circulating chronic lymphocytic leukemia (CLL) cells display an abnormal increase in the surface levels of the homing receptors CCR7 and CXCR4 concomitant with low S1P receptor 1 (S1P1) expression. In this study, we investigated the role of receptor recycling on CXCR4/CCR7 surface levels in CLL cells and addressed the impact of quantitative alterations of these receptors and S1P1 on the ability of leukemic cells to accumulate in SLOs. We show that recycling accounts, to a major extent, for the high levels of surface CXCR4/CCR7 on CLL cells. In addition, increased expression of these receptors, together with S1P1 deficiency, is detectable not only in circulating leukemic cells, but also in SLOs of CLL patients with lymphoadenopathy. We further provide evidence that ibrutinib, a Btk inhibitor that promotes mobilization of leukemic cells from SLOs, normalizes the imbalance between CXCR4/CCR7 and S1P1. Taken together, our results highlight the relevance of chemokine and S1P receptor recycling in CLL pathogenesis and clinical outcome

Clinical and functional impact of recurrent S1PR1 mutations in mantle cell lymphoma

“…25 Patrussi et al reported that ibrutinib elevates expression of S1PR1 (simultaneously decreasing CCR7) in chronic lymphocytic leukemia. 26 However, further studies are needed to determine if S1PR1 mutations impact the outcome of ibrutinib therapy in MCL.…”

Exit Strategies: S1P Signaling and T Cell Migration

“…Ccr7 +/− naïve T cells exit the lymph nodes more quickly than WT, and the failure of S1PR1-deficient T cells to exit lymph nodes can be partially rescued by treatment of the cells with pertussis toxin, which inhibits all Gi protein coupled receptor signaling. In line with these findings, treatment of chronic lymphoblastic leukemia patients with the Btk inhibitor ibrutinib induces lymph node shrinkage and concomitant transient lymphocytosis, which is associated with upregulation of S1PR1 and downregulation of CCR7 on peripheral blood B cells[14]. Recently, it has been demonstrated that the chemokine receptor CXCR4 acts with CCR7 to retain T cells within lymph nodes [15].…”

Role of LFA-1 and ICAM-1 in Cancer

“…The gathering of CLL cells with other stromal cells, macrophages and T cells defines a pseudo-follicle, which supports CLL cell proliferation [33]. The importance of migration and adhesion in determining pathogenesis in this leukemia type is exemplified by treatment with a Bruton tyrosine kinase inhibitor, that mobilizes leukemic cells out of the supportive lymphoid organs resulting in CLL regression [32] [34]. The inhibition of Bruton tyrosine kinase impedes chemokine-and B-cell receptor-derived signaling governing adhesion and migration of CLL cells.…”

“…Circulating normal B cells continuously home to secondary lymphoid organs in search of antigen and to acquire survival signals. Similarly, B-CLL cells take advantage of this survival path by increasing the expression of homing chemokine receptors CXCR4 and CCR7, and decreased expression of the egress receptor S1P1, to home to lymphoid organs, an environment that favors clonal expansion [32]. The gathering of CLL cells with other stromal cells, macrophages and T cells defines a pseudo-follicle, which supports CLL cell proliferation [33].…”