Signaling lymphocyte activation molecule family receptor (SLAMF)

The Signaling Lymphocyte Activation Molecule (SLAM) family receptors comprise nine transmembrane glycoproteins (SLAMF1–SLAMF9) that play a pivotal role in modulating innate and adaptive immune responses through cell-cell interactions [1, 9]. These receptors are primarily expressed on hematopoietic cells and often act as self-ligands, facilitating homotypic or heterotypic adhesion and signaling between lymphocytes, natural killer (NK) cells, and antigen-presenting cells [1, 4]. Their signaling is unique because it is context-dependent, relying on intracellular adaptors like SLAM-associated protein (SAP) and Ewing's sarcoma-associated transcript 2 (EAT-2) [11, 17]. When these adaptors are present, SLAM receptors generally act as activators, whereas their absence can lead to inhibitory signaling, a phenomenon known as a 'switch-of-function' [17]. In oncology, SLAMF7 is a highly validated therapeutic target due to its consistent overexpression in multiple myeloma, leading to the clinical development and approval of elotuzumab [2, 14]. Beyond cancer, the family is involved in autoimmune conditions like systemic lupus erythematosus and acts as a gateway for viral infections, notably with SLAMF1 serving as the entry receptor for the measles virus [1, 15]. Targeted therapies such as monoclonal antibodies and CAR-T cells exploit these receptors to enhance immune cytotoxicity against malignant cells or modulate overactive immune responses in inflammatory diseases [11, 16].

Other names

SLAM familySignaling lymphocytic activation molecule familyCD150 familyCD2 subfamily of the immunoglobulin superfamilySLAMF1-9CS1 (SLAMF7)CD229 (SLAMF3)CD244 (SLAMF4)NTB-A (SLAMF6)

Drugs targeting this family, most notably elotuzumab, primarily function through a dual mechanism: they directly activate natural killer (NK) cells via the EAT-2 signaling pathway and simultaneously tag malignant cells for destruction through antibody-dependent cellular cytotoxicity (ADCC) [2, 10, 14]. Other investigational approaches include blocking inhibitory 'cis' homotypic interactions (e.g., SLAMF6) on T cells to reverse exhaustion, or using antibody-drug conjugates (ADCs) and chimeric antigen receptor (CAR) T cells to selectively lyse SLAM-expressing tumor cells in hematologic malignancies [11, 16, 21].