Nurse-like cells promote CLL survival through LFA-3/CD2 interactions

// Frederic Boissard 1 , Marie Tosolini 1 , Laetitia Ligat 1, 2 , Anne Quillet-Mary 1 , Frederic Lopez 1, 2 Jean-Jacques Fournie 1 , Loic Ysebaert 1, 3, * and Mary Poupot 1, * 1 CRCT UMR1037 INSERM-ERL 5294 CNRS-Universite Toulouse III Paul Sabatier, Toulouse, France 2 Pole Technologique CRCT, Plateau Imagerie, Toulouse, France 3 IUCT-Oncopole, Toulouse, France * These authors contributed equally to this work Correspondence to: Mary Poupot, email: mary.poupot@inserm.fr Loic Ysebaert, email: ysebaert.loic@iuct-oncopole.fr Keywords: tumor associated macrophages, cells cross-talk, cell survival, leukemia Received: September 09, 2016      Accepted: November 18, 2016      Published: November 26, 2016 ABSTRACT In the tumoral micro-environment (TME) of chronic lymphocytic leukemia (CLL), nurse-like cells (NLC) are tumor-associated macrophages which play a critical role in the survival and chemoresistance of tumoral cells. This pro-survival activity is known to involve soluble factors, but few data are available on the relative role of cells cross-talk. Here, we used a transcriptome-based approach to systematically investigate the expression of various receptor/ligand pairs at the surface of NLC/CLL cells. Their relative contribution to CLL survival was assessed both by fluorescent microscopy to identify cellular interactions and by the use of functional tests to measure the impact of uncoupling these pairs with blocking monoclonal antibodies. We found for the first time that lymphocyte function-associated antigen 3 (LFA-3), expressed in CLL at significantly higher levels than in healthy donor B-cells, and CD2 expressed on NLC, were both key for the specific pro-survival signals delivered by NLC. Moreover, we found that NLC/CLL interactions induced the shedding of soluble LFA-3. Importantly, in an exploratory cohort of 60 CLL patients receiving frontline immunochemotherapy, increased levels of soluble LFA-3 were found to correlate with shorter overall survival. Altogether, these data suggest that LFA-3/CD2 interactions promote the survival of CLL cells in the tumor microenvironment.