The microenvironment differentially impairs passive and active immunotherapy in chronic lymphocytic leukaemia - CXCR4 antagonists as potential adjuvants for monoclonal antibodies

Abstract

Direct contact with stromal cells protects chronic lymphocytic leukaemia (CLL) B cells from chemotherapy-induced apoptosis in vitro. Blockade of CXCR4 signalling antagonizes stroma-mediated interactions and restores CLL chemosensitivity. In vivo, administration of CXCR4 antagonists effectively mobilizes haematopoietic progenitor cells. Therefore, combinations of CXCR4 blockade and cytoreductive treatment with selective activity on CLL cells may avoid potential haematotoxicity. 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 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 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 Natural Killer 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.