TY - JOUR
T1 - The CXCR4-STAT3-IL-10 pathway controls the immunoregulatory function of chronic lymphocytic leukemia and is modulated by lenalidomide
AU - Shaim, Hila
AU - Estrov, Zeev
AU - Harris, David
AU - Sanabria, Mayra Hernandez
AU - Liu, Zhiming
AU - Ruvolo, Peter
AU - Thompson, Phillip A.
AU - Ferrajoli, Alessandra
AU - Daher, May
AU - Burger, Jan
AU - Muftuoglu, Muharrem
AU - Imahashi, Nobuhiko
AU - Li, Li
AU - Liu, Enli
AU - Alsuliman, Abdullah Saleh
AU - Basar, Rafet
AU - Kerbauy, Lucila Nassif
AU - Sobieski, Catherine
AU - Gokdemir, Elif
AU - Kondo, Kayo
AU - Wierda, William
AU - Keating, Michael
AU - Shpall, Elizabeth J.
AU - Rezvani, Katayoun
N1 - Publisher Copyright:
© 2018 Shaim, Estrov, Harris, Hernandez Sanabria, Liu, Ruvolo, Thompson, Ferrajoli, Daher, Burger, Muftuoglu, Imahashi, Li, Liu, Alsuliman, Basar, Nassif Kerbauy, Sobieski, Gokdemir, Kondo, Wierda, Keating, Shpall and Rezvani.
PY - 2018/1/15
Y1 - 2018/1/15
N2 - 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.
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.
KW - B10
KW - CXC chemokine ligand 12/CXCR4 axis
KW - Chronic lymphocytic leukemia
KW - IL-10
KW - Immunosuppression
KW - Lenalidomide
KW - Regulatory B cells
KW - STAT3
UR - http://www.scopus.com/inward/record.url?scp=85040838866&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85040838866&partnerID=8YFLogxK
U2 - 10.3389/fimmu.2017.01773
DO - 10.3389/fimmu.2017.01773
M3 - Article
C2 - 29379494
AN - SCOPUS:85040838866
SN - 1664-3224
VL - 8
JO - Frontiers in immunology
JF - Frontiers in immunology
IS - JAN
M1 - 1773
ER -