SLAMF6 in health and disease: Implications for therapeutic targeting

Abstract

Effective immune responses develop after a well-orchestrated series of events that include recognition, immune cell interactions and activation/inhibition of signaling pathways. The signaling lymphocyte activation molecule family (SLAMF) of cell surface receptors, which consists of nine transmembrane proteins (SLAMF1-9) expressed at different levels, are involved in viral and bacterial recognition, serve as co-stimulatory molecules at immune synapses, and modulate myeloid and lymphocyte development. SLAMF receptors are homophilic receptors, with the exception of SLAMF2 and SLAMF4, and are only expressed on hematopoietic cells. Their adaptors, SLAM associated protein (SAP) and Ewing's sarcoma-associated transcript 2 (EAT-2), bind to the cytoplasmic tails and control the functions and magnitude of SLAMF receptor signaling. In this review, we focus on the current knowledge on the role of SLAMF6 receptor in regulating immune functions and recent findings describing how SLAMF6 can be exploited as a target in human malignancies. The SLAM family of immune cell surface receptors is a member of the CD2 subfamily of the immunoglobulin (Ig) superfamily consisting of nine members, SLAMF1-9 [1-4]. SLAMF receptors are type I transmembrane glycoproteins comprised of an extracellular membrane containing an N-terminal V-Ig domain followed by a C2-Ig domain in the extracellular region (this set is duplicated in SLAMF3), a transmembrane region, and an intracellular cytoplasmic tail containing tyrosine based switch motifs (ITSM). Notable exceptions to this structure include SLAMF2, which has a glycosyl-phosphatidyl-inositol (GPI) membrane anchor and like SLAMF8 and SLAMF9 lack ITSM motifs [5-8]. Binding of SLAM associated adaptors; SAP and EAT-2, to cytoplasmic tails of various SLAMFs regulate their function on different immune cells. Expression of SLAMFs and their adaptors is restricted to hematopoietic cells. In addition, the gene loci are located on chromosome 1 in both mice and humans, except SAP, which is located on the X chromosome [9](Figure 1). All SLAMFs are homophilic receptors aside from SLAMF2 and SLAMF4, which bind each other [10-12]. The determination of the SLAMF3, SLAMF5 and SLAMF6 crystal structures revealed in-trans interactions through their IgV domains (SLAMF3 unpublished data, generously donated by Profs. Steve Almo and Stanley Nathenson, Albert Einstein College of Medicine (Figure 2) [13, 14]. Engagement of SLAMF ACCEPTED MANUSCRIPT A C C E P T E D M A N U S C R I P T receptors on immune cells (e.g. APC -T cell) trigger inhibitory or activating signals that modulate cellular responses. Within these homophilic and heterophilic interactions, the binding affinities for each SLAMF varies (SLAMF3 nM, SLAMF5 sub-M, SLAMF6 ~ 2M, SLAMF2/4 ~4M, SLAMF1 ~200 M) which likely contributes to functional differences within the family of receptors [12-15]. In addition to being self-ligands, SLAMF1 also serves as an entry receptor for Measles virus [16, 17] while SLAMF1, SLAMF2 and SLAMF6 have been demonstrated to interact...

SLAMF6 clustering is required to augment T cell activation

“…Furthermore, Yigit et al . has shown that the administration of SLAMF6 antibodies in combination with the BTK kinase inhibitor Ibrutinib has a positive effect on depleting leukemia cells from mice [33]. Given the aforementioned studies we have decided to proceed with SLAMF6 antibodies.…”

SLAMF7 and SLAMF8 receptors shape human plasmacytoid dendritic cell responses to intracellular bacteria

“…SLAMF receptor functions are controlled by the SLAM-associated protein (SAP) family of adaptors, comprising SAP, EAT-2, and ERT, which either block the recruitment of inhibitory phosphatases (like SHP-1 or SHP-2) or directly activate signaling pathways. These interactions dictate the activation or inhibitory nature of the SLAMF receptors upon engagement (41, 42). Here, we found that EAT-2 was highly expressed in CAL-1 cells, stable upon infection with Salmonella and when SLAMF7 or SLAMF8 were down-regulated (Figure 5D).…”

Melphalan flufenamide inhibits osteoclastogenesis by suppressing proliferation of monocytes

“…This immune checkpoint molecule has been shown to control CD8 + T cells and NK cells ( Lee et al, 2017 ). In addition, SLAMF6 is another negative regulator of CD8 + T cell response ( Yigit et al, 2019a ; Yigit et al, 2019b ) up-regulated during osteoclastogenesis. Thus, osteoclasts not only support myeloma cell growth, but they also impede immune responses through several highly expressed negative regulators of immune response including, but not limited to, MMP9, MMP14, B7-H3, PD-L1, and PD-L2.…”