Frontiers in Immunology (Jan 2018)

The CXCR4–STAT3–IL-10 Pathway Controls the Immunoregulatory Function of Chronic Lymphocytic Leukemia and Is Modulated by Lenalidomide

  • Hila Shaim,
  • Zeev Estrov,
  • David Harris,
  • Mayra Hernandez Sanabria,
  • Zhiming Liu,
  • Peter Ruvolo,
  • Phillip A. Thompson,
  • Alessandra Ferrajoli,
  • May Daher,
  • Jan Burger,
  • Muharrem Muftuoglu,
  • Nobuhiko Imahashi,
  • Li Li,
  • Enli Liu,
  • Abdullah Saleh Alsuliman,
  • Rafet Basar,
  • Lucila Nassif Kerbauy,
  • Catherine Sobieski,
  • Elif Gokdemir,
  • Kayo Kondo,
  • William Wierda,
  • Michael Keating,
  • Elizabeth J. Shpall,
  • Katayoun Rezvani

DOI
https://doi.org/10.3389/fimmu.2017.01773
Journal volume & issue
Vol. 8

Abstract

Read online

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.

Keywords