SLAMF7

What is SLAMF7 protein?

SLAMF7 (SLAM family member 7) gene is a protein coding gene which situated on the long arm of chromosome 1 at locus 1q23. SLAMF7, also known as Signaling Lymphocytic Activation Molecule Family Member 7 or CS1, is a protein that is part of the signaling lymphocytic activation molecule (SLAM) family. This family of proteins plays a role in the immune system, particularly in the regulation of immune responses. SLAMF7 is primarily expressed on immune cells, such as natural killer (NK) cells, T cells, and macrophages, and is involved in cell-cell interactions that modulate immune responses. The protein is implicated in various immune functions, including the activation of NK cells and the phagocytosis of hematopoietic tumor cells by macrophages. It is also considered a promising target for immunotherapy, especially in the treatment of multiple myeloma, where it is expressed on the surface of malignant plasma cells. The SLAMF7 protein is consisted of 335 amino acids and its molecular mass is approximately 37.4 kDa.

What is the function of SLAMF7 protein?

It acts as a receptor that triggers immune responses through homo- or heterotypic cell-cell interactions. Mediating NK (natural killer) cell activation in a manner that can be independent of the small cytoplasmic adapter protein SH2D1A/SAP. Positively regulating NK cell functions through a mechanism that involves phosphorylated SH2D1B and downstream signaling implicating PLCG1, PLCG2, and PI3K. It contributs to the phagocytosis of hematopoietic tumor cells by macrophages, which is a process critical for cancer control. This function is independent of SAP adaptors and instead depends on SLAMF7's ability to interact with integrin Mac-1 and utilize signals involving immunoreceptor tyrosine-based activation motifs.

Fig1. Resistance mechanism theories for elotuzumab. (Emily Chu, 2023)

SLAMF7 Related Signaling Pathway

SLAMF7 is critical for the phagocytosis of hematopoietic tumor cells via the interaction with Mac-1 integrin on macrophages, which is a process that can be enhanced by the blockade of the SIRPα-CD47 checkpoint, a mechanism that cancer cells exploit to evade anti-tumor immunity. SLAMF7 mediates NK cell activation through a pathway that can be independent of the SH2D1A/SAP adaptors. SLAMF7 engagement can superactivate macrophages, enhancing their ability to eliminate tumor cells in acute myeloid leukemia. This suggests a role for SLAMF7 in modulating the activity of macrophages, which are key players in the tumor microenvironment. The homotypic interaction of SLAMF7 on both immune and tumor cells can influence tumor progression and the effectiveness of the immune response against the tumor.

SLAMF7 Related Diseases

SLAMF7 is associated with a variety of diseases, especially with hematologic tumors. SLAMF7 expression is significantly upregulated in patients with Multiple Myeloma, and the SLAMF7 gene is frequently amplified in the progressive form of the disease. The SLAMF7 monoclonal antibody Elotuzumab has shown positive results in the treatment of multiple myeloma by promoting the phagocytosis and presentation of tumors by immune cells. In addition, SLAMF7 is also upregulated in Plasmablastic Lymphoma and may serve as a biomarker for adjuvant diagnosis. In colorectal cancer, downregulation of SLAMF7 expression levels is associated with tumor progression and metastasis. Increased serum SLAMF7 concentrations have also been found to be associated with the progression of multiple myeloma and may serve as an indicator to assist in diagnosis and monitoring of disease progression.

Bioapplications of SLAMF7

SLAMF7 is expressed on a variety of immune cells, including NK cells, T cells, etc. Therefore, it has potential applications in immune cell therapy, such as through chimeric antigen receptor (CAR) T cell therapy or NK cell therapy to enhance the specific killing of tumor cells. The high expression of SLAMF7 in multiple myeloma makes it a novel biomarker to assist in the diagnosis of the disease, and changes in serum SLAMF7 levels can also serve as a monitoring indicator of disease progression and treatment response. Targeted therapies for SLAMF7 are being developed for other tumor types, and their mechanisms of action in the tumor immune microenvironment are being studied to identify new therapeutic opportunities. SLAMF7 is involved in the activation and regulation of immune cells, so it may play a role in the development of new immunomodulatory drugs to enhance or suppress the immune response.

Case Study 1: Christina Amatya, 2021

Chimeric antigen receptors (CARs) are fusion proteins that contain antigen-recognition domains and T cell signaling domains. Signaling lymphocytic-activation molecule F7 (SLAMF7) is a promising target for CAR T cell therapies of the plasma cell malignancy multiple myeloma (MM) because SLAMF7 is expressed by MM but not normal nonhematopoietic cells. Researchers designed CARs targeting SLAMF7. They transduced human T cells with anti-SLAMF7 CARs containing either CD28 or 4-1BB costimulatory domains. T cells expressing CD28-containing CARs or 4-1BB-containing CARs recognized recombinant SLAMF7 in vitro. SLAMF7-specific cytokine release was higher for T cells expressing CARs with CD28 versus 4-1BB domains. In murine solid tumor and disseminated tumor models, anti-tumor activity of T cells was superior with CD28-containing CARs versus 4-1BB-containing CARs. Because of SLAMF7 expression on some normal leukocytes, especially natural killer cells that control certain viral infections, the inclusion of a suicide gene with an anti-SLAMF7 CAR is prudent.

Fig1. Percentages of each cell type that expressed SLAMF7 are shown.

Fig2. T cells were labeled with CFSE and cultured with either SLAMF7-K562 cells or NGFR-K562 cells for 4 days.

Case Study 2: Uyory Choe, 2023

To further elucidate the expression, regulation and function of Signaling Lymphocytic Activation Molecule Family (SLAMF) protein members in human monocytes and macrophages. Un-differentiated monocytic THP-1 cell (u-THP-1) and differentiated THP-1 macrophage (d-THP-1) were used as culture models in the study. Responses of cells to the differentiation agents phorbol ester (25 ng/ml) and TLR (Toll-like receptor) ligands were assessed. RT-PCR and Western blot analysis were used to determine mRNA and protein level. Pro-inflammatory cytokine mRNA expression levels and phagocytosis were used as functional markers. Data analyzed using t-test, one-way or two-way ANOVA followed by post hoc test. SLAMFs were differentially expressed in THP-1 cells. Differentiation of u-THP-1 to d-THP-1 led to significantly higher SLAMF7 mRNA and protein levels than other SLAMF. In addition, TLR stimuli increased SLAMF7 mRNA expression but not protein expression. Importantly, SLAMF7 agonist antibody and TLR ligands synergistically increased the mRNA expression levels of IL-1β, IL-6 and TNF-α, but had no effect on phagocytosis.

Fig3. Western blot analysis of SLAMF7 protein expression.

Fig4. Effects of SLAMF7 antibody on phagocytosis activity of macrophage.

SLAMF7 has several biochemical functions, for example, chromatin DNA binding,protein binding,sequence-specific DNA binding. Some of the functions are cooperated with other proteins, some of the functions could acted by SLAMF7 itself. We selected most functions SLAMF7 had, and list some proteins which have the same functions with SLAMF7. You can find most of the proteins on our site.

SLAMF7 has direct interactions with proteins and molecules. Those interactions were detected by several methods such as yeast two hybrid, co-IP, pull-down and so on. We selected proteins and molecules interacted with SLAMF7 here. Most of them are supplied by our site. Hope this information will be useful for your research of SLAMF7.

MAK;CLK3;TRIB2