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

The TAM receptors— TYRO3, AXL, MERTK—are pleiotropically expressed receptorsin both healthy and diseased tissue. A complex of the ligands Protein S(PROS1) or Growth Arrest-Specific 6 ( GAS6) with apoptotic phosphatidylserineactivates the TAM receptors. Hence, this receptorfamily is essential for the efferocytosisof apoptotic material by antigen-presenting cells. In addition, TAM receptorsare 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 receptorshave emerged as promising targets for cancer therapy. Recently, TAM receptorshave 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 receptorsin the tumor microenvironment. We place particular focus on TAM receptorsand the recently unraveled role of MERTKin activated T cells and potential consequences for anti-tumor immunity.