PMID- 29379494 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20191120 IS - 1664-3224 (Print) IS - 1664-3224 (Electronic) IS - 1664-3224 (Linking) VI - 8 DP - 2017 TI - The CXCR4-STAT3-IL-10 Pathway Controls the Immunoregulatory Function of Chronic Lymphocytic Leukemia and Is Modulated by Lenalidomide. PG - 1773 LID - 10.3389/fimmu.2017.01773 [doi] LID - 1773 AB - 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. FAU - Shaim, Hila AU - Shaim H AD - Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. FAU - Estrov, Zeev AU - Estrov Z AD - Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. FAU - Harris, David AU - Harris D AD - Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. FAU - Hernandez Sanabria, Mayra AU - Hernandez Sanabria M AD - Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. FAU - Liu, Zhiming AU - Liu Z AD - Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. FAU - Ruvolo, Peter AU - Ruvolo P AD - Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. FAU - Thompson, Phillip A AU - Thompson PA AD - Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. FAU - Ferrajoli, Alessandra AU - Ferrajoli A AD - Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. FAU - Daher, May AU - Daher M AD - Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. FAU - Burger, Jan AU - Burger J AD - Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. FAU - Muftuoglu, Muharrem AU - Muftuoglu M AD - Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. FAU - Imahashi, Nobuhiko AU - Imahashi N AD - Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. FAU - Li, Li AU - Li L AD - Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. FAU - Liu, Enli AU - Liu E AD - Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. FAU - Alsuliman, Abdullah Saleh AU - Alsuliman AS AD - Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. FAU - Basar, Rafet AU - Basar R AD - Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. FAU - Nassif Kerbauy, Lucila AU - Nassif Kerbauy L AD - Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. FAU - Sobieski, Catherine AU - Sobieski C AD - Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. FAU - Gokdemir, Elif AU - Gokdemir E AD - Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. FAU - Kondo, Kayo AU - Kondo K AD - Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. FAU - Wierda, William AU - Wierda W AD - Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. FAU - Keating, Michael AU - Keating M AD - Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. FAU - Shpall, Elizabeth J AU - Shpall EJ AD - Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. FAU - Rezvani, Katayoun AU - Rezvani K AD - Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States. LA - eng GR - P30 CA016672/CA/NCI NIH HHS/United States PT - Journal Article DEP - 20180115 PL - Switzerland TA - Front Immunol JT - Frontiers in immunology JID - 101560960 PMC - PMC5775272 OTO - NOTNLM OT - B10 OT - CXC chemokine ligand 12/CXCR4 axis OT - IL-10 OT - STAT3 OT - chronic lymphocytic leukemia OT - immunosuppression OT - lenalidomide OT - regulatory B cells EDAT- 2018/01/31 06:00 MHDA- 2018/01/31 06:01 PMCR- 2017/01/01 CRDT- 2018/01/31 06:00 PHST- 2017/09/18 00:00 [received] PHST- 2017/11/28 00:00 [accepted] PHST- 2018/01/31 06:00 [entrez] PHST- 2018/01/31 06:00 [pubmed] PHST- 2018/01/31 06:01 [medline] PHST- 2017/01/01 00:00 [pmc-release] AID - 10.3389/fimmu.2017.01773 [doi] PST - epublish SO - Front Immunol. 2018 Jan 15;8:1773. doi: 10.3389/fimmu.2017.01773. eCollection 2017.