SLAMF6 signaling in murine chronic lymphocytic leukemia cells (TUM2P.1019)

Chronic lymphocytic leukemia (CLL) is a circulating B cell tumor that initiates in the bone marrow and blood and spreads to the lymph nodes, liver and spleen. Disease pathogenesis is largely characterized by hyper-activation of B cell receptor (BCR) signaling and subsequent tumor accumulation in the secondary lymphoid organs. Targeting BCR downstream pathways with small inhibitor molecules, e.g. ibrutinib (an irreversible BTK inhibitor), shows great efficacy in the clinic. However, there is still a need for additional therapeutic targets for CLL, as patients eventually relapse. Because the homophilic cell surface receptor Slamf6 is highly expressed on CLL cells and plays a role in T FH - B cell interactions, the effects of anti-Slamf6 on the murine CLL cell line TCL1-192 was assessed. To this end SCID mice that had been transplanted with TCL1-192 received injections of mouse anti-Slamf6 (13G3) monoclonal antibody or isotype control. Injection of anti-Slamf6 significantly reduced tumor burden in the blood and spleen. This response is due to ADCC as well as to Slamf6 signaling as injections of F(ab’) 2 fragments of anti-Slamf6 antibody results in down-regulation of proximal BCR components (pSyk, pBtk). Additionally, anti-Slamf6 resulted in a block in TCL1-192 tumor migration from the peritoneum to the blood and spleen. Overall, this study suggests that Slamf6 could be a potential new target for CLL therapy.