Clever-1 (Common lymphatic endothelial and vascular endothelial receptor-1, also known as Stab1, Feel-1, and Stabilin-1), is a large and multifunctional glycoprotein receptor. It is expressed by sinusoidal endothelial cells in the adrenal cortex, liver, lymph nodes, and spleen. Indeed, the Clever-1 is expressed on the efferent and afferent arms of the lymph node lymphatic endothelium, subsets of immunosuppressive macrophages and circulating monocytes to a greater extent. Furthermore, pregnant women's placental macrophages also abundantly express the Clever-1, and this has been considered to promote immunosuppression allowing the mother's immune system to tolerate fetal antigens. Clever-1 is an acknowledged scavenger receptor that plays a role in the scavenging of apoptotic cells and molecules, and potential cancer antigens. Meanwhile, it is involved in angiogenesis, cell adhesion, and lymphocyte transmigration.
Clever-1 is encoded by the gene named Stab1, and the genomic nucleotide sequencing suggested that Clever-1 is a very large (approximately 270-280 kDa) and high evolutionary conservation type-I transmembrane protein with a large extracellular multidomain nature containing one X-link homology region, seven fascicles-like domains, and numerous EGF-like domains (act the function of cell/matrix interactions and homotypic adhesion). Stab1 contains 69 exons, which provides several potentialities for alternative splicing, and there are more than two isoforms of Clever-1 that have been found at the protein level and may manifest as cell-type specific.
Clever-1 with its distinctive ligand involved in sophisticated physiological clearance processes. For example, clever-1 can bind, internalize, and target degradation-modified forms of LDL, such as oxLDL and its analog acetylated acLDL using the classical endocytic pathway for the trafficking of extracellular ligands. Clever-1 performed the function of internalizing and clearing of secreted protein acidic and rich in cysteine (SPARC, a universal regulate molecule of tissue remodeling) through the extracellular EGF-like domain containing the sequence FHGTAC. Clever-1 plays the function of prohibiting the immune response against the tumors cells by mediating a fast removal and degradation action of those self-unneeded components including SPARC, underlying cancer antigens, advanced glycation end products (AGEs), and so on.
Clever-1 normally acts as an immunosuppressive molecule on monocyte by directly or indirectly regulates the ability of monocytes to polarise T cells into Th1 upon the stimulation of antigens. Recent studies also highlight its immunologic impact on tumor-associated macrophage (TAM) polarization. The blocking of Clever-1 expression on monocytes or macrophages appears a transformation, a change from the immunosuppressive M2 macrophages to the immunostimulatory M1 macrophages. This transformation has the ability to promote the macrophages to produce more TNF-α and support antibody production. Moreover, recent ex vivo and In vivo studies on vascular and lymphatic endothelial cells have shown that Clever-1 is involved in lymphocyte transmigration, and can mediate leukocyte and cancer cell trafficking via the lymphatic system into the draining lymph nodes and lymphocyte homing to the spleen.
Fig.1 A schematic representation of multiple functions of Clever-1.1,2
Clever-1 is a very versatile molecule, and there is much preclinical evidence unveiling that targeting Clever-1 is active in innate and adaptive T cell responses, and the clever-1 blocking agent targeting tumor immunotherapy has been particularly attractive in recent years. Studies in multiple solid tumor models found that removal of the clever-1 from macrophages can significantly delay tumor growth, implying clever-1 as a novel target in clinical cancer evaluation and immunotherapy. There are already some clever-1 inhibitors involving solid tumors currently in phase I/II clinical trials.
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