Data from CD126 and Targeted Therapy with Tocilizumab in Chronic Lymphocytic Leukemia

Abstract

<div>Abstract<p><b>Purpose:</b> IL6 promotes tumor growth and signal transduction via both its membrane-bound (CD126) and soluble receptors (sCD126). We aimed to study whether the levels of CD126 expression in chronic lymphocytic leukemic (CLL) cells can predict <i>in vitro</i> and <i>in vivo</i> treatment response.</p><p><b>Experimental Design:</b> The levels of membrane-bound CD126 expression were determined on freshly isolated CLL B cells (<i>n</i> = 58) using flow cytometry. These CLL cells were treated with chlorambucil or fludarabine with or without anti-CD126 antibody tocilizumab for 24 hours and IL6-mediated STAT3 transcriptional activity and cell-cycle alteration were evaluated.</p><p><b>Results:</b> CD126 surface expression was found in all cases and positively correlated with the levels of <i>in vivo</i> constitutive STAT3 activity. The levels of CD126 expression were significantly and positively correlated with the resistance of CLL cells to <i>in vitro</i> treatment with chlorambucil or fludarabine and poor <i>in vivo</i> treatment response of CLL patients. Blocking IL6 signaling with the anti-CD126 antibody, tocilizumab, had profound effects on STAT3-mediated survival and growth signals: decreased Mcl-1 and Bcl-xL, favoring an apoptotic profile; and decreased p27 with increased cyclin E and CDK2 expression, leading to cell-cycle shift from G<sub>0</sub>–G<sub>1</sub>. These tocilizumab-mediated changes induced chemosensitization in resistant CLL cells, with the greatest effect seen in cells with higher CD126 expression (<i>P</i> < 0.001).</p><p><b>Conclusions:</b> CLL cells with higher CD126 expression are more resistant to treatment <i>in vivo</i> and <i>in vitro</i> via IL6–CD126–STAT3 axis. Blocking CD126 using tocilizumab sensitizes CLL cells to chemotherapy. <i>Clin Cancer Res; 22(10); 2462–9. ©2015 AACR</i>.</p></div>