TAM-ing T cells in the tumor microenvironment: implications for TAM receptor targeting

Abstract

The TAM receptors—TYRO3, AXL, MERTK—are pleiotropically expressed receptors in both healthy and diseased tissue. A complex of the ligands Protein S (PROS1) or Growth Arrest-Specific 6 (GAS6) with apoptotic phosphatidylserine activates the TAM receptors. Hence, this receptor family is essential for the efferocytosis of apoptotic material by antigen-presenting cells. In addition, TAM receptors are expressed by virtually all cells of the tumor microenvironment. They are also potent oncogenes, frequently overexpressed in cancer and involved in survival and therapy resistance. Due to their pro-oncogenic and immune-inhibitory traits, TAM receptors have emerged as promising targets for cancer therapy. Recently, TAM receptors have been described to function as costimulatory molecules on human T cells. TAM receptors’ ambivalent functions on many different cell types therefore make therapeutic targeting not straight-forward. In this review we summarize our current knowledge of the function of TAM receptors in the tumor microenvironment. We place particular focus on TAM receptors and the recently unraveled role of MERTK in activated T cells and potential consequences for anti-tumor immunity.

Role of Vitamin K-Dependent Factors Protein S and GAS6 and TAM Receptors in SARS-CoV-2 Infection and COVID-19-Associated Immunothrombosis

“…Nevertheless, inflammatory regulation by TAMs is not restricted to innate immunity [ 35 ]. A recent publication reported MERTK expression in T-cells after three days of TCR activation [ 36 , 37 ], in contrast to previous studies [ 38 , 39 ].…”

CD14+CD16− monocytes are the main precursors of osteoclasts in rheumatoid arthritis via expressing Tyro3TK

“…Tyro3 tyrosine kinase (Tyro3TK) is one of the family members of TAM (Tyro3TK, AxlTK, MerTK) receptor tyrosine kinases (RTKs) [ 15 ], which could be expressed on the plasma membrane of a variety of cells, such as monocytes/macrophages, dendritic cells, NK cells, and nerve cells [ 16 ]. Tyro3TK could regulate the clearance of apoptotic cells, cytokine production, cell proliferation, thrombus formation, and hematopoiesis by binding to its ligand growth arrest-specific protein 6 (Gas6) and protein S (ProS1) [ 17 , 18 ]. It was reported that Gas6 is expressed in RA synovium tissue and fluid and plays a role in RA synovium endothelial cell survival [ 19 ].…”

Crystal Structure of the Kinase Domain of MerTK in Complex with AZD7762 Provides Clues for Structure-Based Drug Development

“…Proteins in the TAM family possess extracellular, transmembrane, and conserved kinase domains [ 2 ]. Although TAM family proteins share the common biological ligand growth-arrest-specific 6 (Gas6) for their functional activation [ 3 ], MerTK can also recognize other ligands, such as protein S and galectin-3, through its extracellular immunoglobulin and fibronectin-like domains [ 2 , 4 , 5 ]. The binding of these ligands to MerTK induces the autophosphorylation of tyrosine residues in the activation loop of the MerTK kinase domain (Tyr749, Tyr753, and Tyr754) [ 6 ], resulting in the recruitment of adaptor proteins including Grb2, LimD4, and Vav1 [ 7 , 8 , 9 , 10 ], and the activation of downstream enzymes such as PI3Ks, MAPKs, and GTPases [ 2 , 7 ].…”