Idit Shachar Lab

Multiple sclerosis (MS) is a chronic neurological disorder characterized by demyelination of the central nervous system (CNS), leading to a broad spectrum of physical and cognitive impairments. Myeloid cells within the CNS, including microglia and border-associated macrophages, play a central role in the neuroinflammatory processes associated with MS. Activation of these cells contributes to the local inflammatory response and promotes the recruitment of additional immune cells into the CNS. SLAMF5 is a cell surface receptor that functions as a homophilic adhesion molecule, capable of modulating immune cell activity through both activating and inhibitory signals. In this study, we investigated the expression and function of SLAMF5 in CNS-resident and peripheral myeloid cells using the murine model of MS experimental autoimmune encephalomyelitis (EAE). Our findings demonstrate that both total and brain-specific SLAMF5 deficiency in myeloid cells leads to decreased expression of activation and costimulatory molecules, including MHC class II (MHCII) and CD80. This downregulation is mediated, at least in part, through the transcription factor BHLHE40 and its regulation of CD52, resulting in delayed onset and reduced progression of the disease. Furthermore, pharmacological blockade of SLAMF5 in the brain halted disease progression and reduced the expression of myeloid activation markers. In human studies, SLAMF5 blockade in peripheral monocytes from MS patients and in induced pluripotent stem cell (iPSC)-derived microglia reduced the expression of HLA-DR, CD80, and CD52. Together, these results identify SLAMF5 as a key regulator of myeloid cell activation in neuroinflammation and suggest that it may represent a promising therapeutic target for autoimmune disorders such as MS.

Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype. The tumor microenvironment (TME) plays a major regulatory role in TNBC progression and is highly infiltrated by suppressive immune cells that reduce anti-tumor immune activity. Although regulatory B cells (Bregs) are a key TME component, knowledge of their function in TNBC is limited. CD84 is a homophilic adhesion molecule that promotes the survival of blood tumors. In the current study, we followed the role of CD84 in the regulation of the TME in TNBC. We demonstrate that CD84 induces a cascade in Bregs that involves the β-catenin and Tcf4 pathway, which induces the transcription of interleukin-10 by binding to its promoter and the promoter of its regulator, AhR. This leads to the expansion of Bregs, which in turn control the activity of other immune cells and immune suppression. Accordingly, we suggest CD84 as a therapeutic target for breaking immune tolerance in TNBC.

CD74 is a cell-surface receptor for the cytokine macrophage migration inhibitory factor (MIF). MIF binding to CD74 induces a signaling cascade resulting in the release of its cytosolic intracellular domain (CD74-ICD), which regulates transcription in naïve B and chronic lymphocytic leukemia (CLL) cells. In the current study, we investigated the role of CD74 in the regulation of the immunosuppressive tumor microenvironment (TME) in triple-negative breast cancer (TNBC). TNBC is the most aggressive breast cancer subtype and is characterized by massive infiltration of immune cells to the tumor microenvironment, making this tumor a good candidate for immunotherapy. The tumor and immune cells in TNBC express high levels of CD74; however, the function of this receptor in the tumor environment has not been extensively characterized. Regulatory B cells (Bregs) and tolerogenic dendritic cells) tol-DCs (were previously shown to attenuate the antitumor immune response in TNBC. Here, we demonstrate that CD74 enhances tumor growth by inducing the expansion of tumor-infiltrating tol-DCs and Bregs. Utilizing CD74-KO mice, Cre-flox mice lacking CD74 in CD23⁺ mature B cells, mice lacking CD74 in the CD11c⁺ population, and a CD74 inhibitor (DRQ), we elucidate the mechanism by which CD74 inhibits antitumor immunity. MIF secreted from the tumor cells activates CD74 expressed on DCs. This activation induces the binding of CD74-ICD to the SP1 promotor, resulting in the up-regulation of SP1 expression. SP1 binds the IL-1β promotor, leading to the down-regulation of its transcription. The reduced levels of IL-1β lead to decreased antitumor activity by allowing expansion of the tol-DC, which induces the expansion of the Breg population, supporting the cross-talk between these 2 populations. Taken together, these results suggest that CD74⁺ CD11c⁺ DCs are the dominant cell type involved in the regulation of TNBC progression. These findings indicate that CD74 might serve as a novel therapeutic target in TNBC.