The molecular mechanisms regulating the cross talk between CLL cells and their microenvironment”

Chronic lymphocytic leukemia (CLL), the most common leukemia in the Western world, is characterized by the progressive accumulation of small, mature CD5+ B lymphocytes in the peripheral blood, lymphoid organs and bone marrow (BM). The hallmark of the disease is mainly decreased apoptosis, resulting in accumulation of these malignant cells. Immunosuppression is a prevailing clinical feature in CLL patients, with many patients demonstrating increased susceptibility to infections, as well as increased failure of an intrinsic anti-tumor immune response. However, little is currently known regarding the precise mechanisms that cause this immunosuppressive phenotype in CLL.

Dynamic interactions between cell-surface molecules orchestrate the immune response. The signaling lymphocyte activation molecule (SLAM) family includes nine receptors that modulate the immune responses by homophilic and heterophilic interactions. CD84 is a member of the SLAM family. It is a cell-surface protein, which forms homophilic dimers by self-association. Our studies have previously characterized a novel survival pathway in CLL regulated by CD84. In addition, we recently showed that CD84 serves as an important bridge mediating the interaction between CLL and the various cells in their microenvironment in vitro and in vivo.

Furthermore, we show that a cell-cell interaction mediated through human and mouse CD84 upregulates PD-L1 expression on CLL and their microenvironment, and PD-1 expression on T cells. This results in suppression of T cell response and activity in vitro and in vivo. Thus, our results demonstrate a novel role for CD84 in regulation of immune checkpoints by leukemia cells, and suggest CD84 blockade as a novel therapeutic strategy to reverse tumor-induced immune suppression.