The microenvironment differentially impairs passive and active immunotherapy in Chronic lymphocytic leukemia - Potential therapeutic synergism of CXCR4 antagonists

Maike Buchner (1) , Philipp Brantner (1) , Gabriele Prinz (1) , Meike Burger (1) , Constance Baer (1) , Christine Dierks (1) , Dietmar Pfeifer (1) , Roland Mertelsmann (1) , John G Gribben (2) , Hendrik Veelken (1) , Katja Zirlik (3)

1 Medical Department I
2 Institute of Cancer
3 Medical Department I

Direct contact with stromal cells protects chronic lymphocytic leukemia (CLL) B cells from chemotherapy-induced apoptosis in vitro. Blockade of CXCR4 signaling antagonizes stroma-mediated interactions and restores CLL chemosensitivity. In vivo, administration of CXCR4 antagonists may also effect efficient mobilization of hematopoetic progenitor cells. Therefore, combinations of CXCR4 blockade with cytoreductive treatment with selective activity on CLL cells may avoid potential hematotoxicity. Hence, we tested CXCR4 antagonists in the context of passive and active immunotherapeutic approaches. We evaluated how efficiently rituximab, alemtuzumab, and cytotoxic T cells killed CLL cells cocultured with stromal cells in the presence and absence of a CXCR4 antagonist. Stromal cell contact attenuated rituximab- and alemtuzumab-induced complement-dependent cytotoxicity (CDC) of CLL cells. Addition of CXCR4 antagonists abrogated the protective effect of stroma. In contrast, stromal cells did not impair antibody-dependent cell-mediated cytotoxicity (ADCC) and cytotoxicity induced by activated T cells. Destruction of microtubules in CLL target cells restored the protective effect of stroma coculture for CLL cells during NK cell attack by preventing mitochondrial relocalization towards the immunological synapse. Our data identify the combination of CXCR4 antagonists with passive - but not active - immunotherapy as a promising potential treatment concept in CLL.

Mots clés: Medicine

Maike Buchner, Philipp Brantner, Gabriele Prinz, Meike Burger, Constance Baer, et al.. The microenvironment differentially impairs passive and active immunotherapy in Chronic lymphocytic leukemia - Potential therapeutic synergism of CXCR4 antagonists. British Journal of Haematology, 2010, 151 (2), pp.167. ⟨10.1111/j.1365-2141.2010.08316.x⟩. ⟨hal-00569407⟩