Abstract
Chronic lymphocytic leukemia (CLL) cells possess regulatory functions comparable to those of normal B10 cells, a regulatory B cell subset that suppresses effector T-cell function through STAT3-mediated IL-10 production. However, the mechanisms governing IL-10 production by CLL cells are not fully understood. Here, we show that the CXC chemokine ligand 12 (CXCL12)–CXCR4–STAT3 axis regulates IL-10 production by CLL cells and their ability to suppress T-cell effector function through an IL-10 mediated mechanism. Knockdown of STAT3 significantly impaired the ability of CLL cells to produce IL-10. Furthermore, experiments to assess the role of lenalidomide, an immunomodulatory agent with direct antitumor effect as well as pleiotropic activity on the immune system, showed that this agent prevents a CXCL12-induced increase in p-S727-STAT3 and the IL-10 response by CLL cells. Lenalidomide also suppressed IL-10-induced Y705-STAT3 phosphorylation in healthy T cells, thus reversing CLL-induced T-cell dysfunction. We conclude that the capacity of CLL cells to produce IL-10 is mediated by the CXCL12–CXCR4–STAT3 pathway and likely contributes to immunodeficiency in patients. Lenalidomide appears to be able to reverse CLL-induced immunosuppression through including abrogation of the CXCL12–CXCR4–S727–STAT3-mediated IL-10 response by CLL cells and prevention of IL-10-induced phosphorylation of Y705-STAT3 in T cells.
Highlights
Chronic lymphocytic leukemia (CLL) is characterized by generalized immune suppression and susceptibility to infectious complications and secondary malignancies [1,2,3]
We found that CXCR4 expression on the surface of CLL cells positively correlates with their ability to secrete IL-10 in response to CXC chemokine ligand 12 (CXCL12) stimulation (Figure S5 in Supplementary Material), suggesting that CXCR4 expression could serve as a predictor of CXCL12-induced IL-10 response in CLL
Lenalidomide alone had no effect on healthy T cells function (Figure S10 in Supplementary Material). These findings indicate that lenalidomide can reverse CLL-induced immunosuppression through abrogation of the CXCL12–CXCR4–IL-10–STAT3 response in CLL cells and prevention of T-cell suppression
Summary
Chronic lymphocytic leukemia (CLL) is characterized by generalized immune suppression and susceptibility to infectious complications and secondary malignancies [1,2,3]. A number of studies have reported both quantitative and qualitative defects in T-cell function in CLL [4, 5], the mechanisms underlying CLL-induced immunosuppression have been difficult to dissect, as. The CXCR4–STAT3–IL-10 Axis in CLL they involve complex bidirectional interactions among leukemic cells, components of the tumor microenvironment and immune effectors [6,7,8,9,10]. DiLillo et al [21] recently reported that CLL cells are capable of secreting IL-10 and possess regulatory functions comparable to those of normal B10 cells. IL-10 is elevated in the serum of CLL patients [22] These intriguing observations suggest a means by which CLL cells could induce immunosuppression in patients; but a mechanistic basis for IL-10 production by CLL cells is still lacking
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