AUTHOR=Shaim Hila , Estrov Zeev , Harris David , Hernandez Sanabria Mayra , Liu Zhiming , Ruvolo Peter , Thompson Phillip A. , Ferrajoli Alessandra , Daher May , Burger Jan , Muftuoglu Muharrem , Imahashi Nobuhiko , Li Li , Liu Enli , Alsuliman Abdullah Saleh , Basar Rafet , Nassif Kerbauy Lucila , Sobieski Catherine , Gokdemir Elif , Kondo Kayo , Wierda William , Keating Michael , Shpall Elizabeth J. , Rezvani Katayoun TITLE=The CXCR4–STAT3–IL-10 Pathway Controls the Immunoregulatory Function of Chronic Lymphocytic Leukemia and Is Modulated by Lenalidomide JOURNAL=Frontiers in Immunology VOLUME=8 YEAR=2018 URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2017.01773 DOI=10.3389/fimmu.2017.01773 ISSN=1664-3224 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.