CD84 mediates CLL-microenvironment interactions

Abstract

Chronic lymphocytic leukemia (CLL) is a malignant disease of small mature lymphocytes. Signals from the CLL microenvironment promote progression of the disease and induce drug resistance. This phenomenon is largely dependent on direct contact between the malignant B cells and stromal cells. CD84 belongs to the signaling lymphocyte activation molecule family of immunoreceptors, which self-associates, forming an orthogonal homophilic dimer. We therefore hypothesized that CD84 may bridge between CLL cells and their microenvironment, promoting cell survival. Our in vitro results show that CD84 expressed on CLL cells interact with CD84 expressed on cells in their microenvironment, inducing cell survival in both sides. Blocking CD84 in vitro and in vivo disrupt the interaction of CLL cells with their microenvironment, resulting in induced cell death. Thus, our findings suggest novel therapeutic strategies based on the blockade of this CD84-dependent survival pathway.

Defining the emergence of myeloid-derived suppressor cells in breast cancer using single-cell transcriptomics

“…Here, we identify CD84 and Jaml as novel cell surface receptors on MDSCs, which can be used in combination with CD11b/Gr1 staining to detect the presence of MDSCs in various organs of tumor-bearing mice, or in human in combination with CD11b/CD14 or CD15. CD84 is involved in cell-cell interactions and modulation of the activation and differentiation of a variety of immune cells 49 , and functions as a homophilic adhesion molecule on B cells, monocytes and, on a lower extent, T cells where it enhances IFNg secretion and activation 43,44 . Interestingly, CD84 can regulate PD-1/PD-L1 expression and function in chronic lymphocytic leukemia resulting in suppression of T cell responses and activity 50 , suggesting that CD84 may allow MDSCs to directly regulate immune checkpoints in breast cancer patients.…”

“…Our scRNAseq data revealed several previously unknown specific cell surface markers for MDSCs including CD84 and Amica1/Jaml. CD84 is a cell surface receptor of the signaling lymphocytic activation molecule (SLAM) family 42 and is expressed on some immune cell types 43,44 . Amica1/Jaml is a junctional adhesion molecule known to mediate the transmigration of neutrophils and monocytes by interacting with coxsackie-adenovirus receptor (CAR) expressed by epithelia 45 .…”

CD74 is a novel transcription regulator

“…CD74 siRNA was introduced by electroporation using a Nepagene (Ichikawa) as previously described (47). Sequences are listed in SI Materials and Methods.…”

T Cells Regulate Peripheral Naive Mature B Cell Survival by Cell–Cell Contact Mediated through SLAMF6 and SAP

“…Additional SLAM family members have been implicated in survival of specific B cell populations; SLAMF5 (CD84) induces survival of CLL cells, which upregulate its expression in a CD74/MIF dependent manner (12, 33). SLAMF1 (CD150) regulates apoptosis, proliferation and differentiation and IgG synthesis of B cells (44, 45).…”

“…Data analysis was performed as previously described (33), using Graphpad Prism (Version 6.0f, GraphPad Software Inc., La Jolla, CA, USA). Data are reported as mean +/− SEM.…”