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Ibrutinib inhibits CD20 up-regulation on CLL B cells mediated by the CXCR4/SDF-1 axis

Gabriela Pavlasova, Marek Borsky, Vaclav Seda, Katerina Cerna, Jitka Osickova, Michael Doubek, Jiri Mayer, Raffaele Calogero, Martin Trbusek, Sarka Pospisilova, Matthew S. Davids, Thomas J. Kipps, Jennifer R. Brown and Marek Mraz

Key points

  • Microenvironmental interactions up-regulate CD20 expression in CLL cells through the CXCR4/SDF-1 axis.

  • Ibrutinib treatment causes down-regulation of CD20 in CLL cells.

Abstract

Agents targeting B cell receptor (BCR) signaling-associated kinases such as BTK or PI3K can induce mobilization of neoplastic B cells from the lymphoid tissues into the blood, which makes them potentially ideal to combine with anti-CD20 monoclonal antibodies (such as rituximab or ofatumumab) for treatment of B cell lymphomas and chronic lymphocytic leukemia (CLL). Here we show that interactions between leukemia cells and stromal cells (HS-5) up-regulate CD20 on CLL cells and that administering ibrutinib down-modulates CD20 expression in vivo. We observed that CLL cells that have recently exited the lymph node microenvironment and moved into the peripheral blood (CXCR4dimCD5bright subpopulation) have higher cell surface levels of CD20 than the cells circulating in the bloodstream for a longer time (CXCR4brightCD5dim cells). We found that CD20 is directly up-regulated by CXCR4 ligand SDF-1α (CXCL12) produced by stromal cells, and BTK-inhibitor ibrutinib and CXCR4-inhibitor plerixafor block SDF-1α mediated CD20 up-regulation. Ibrutinib also down-modulated Mcl1 levels in CLL cells in vivo and in co-culture with stromal cells. Overall, our study provides a detailed mechanistic explanation of CD20 expression regulation in the context of microenvironmental interactions and that it may have important implications for microenvironment-targeting therapies.

  • Submitted April 5, 2016.
  • Accepted July 19, 2016.