Targeting Tyro3, Axl and MerTK (TAM receptors): implications for macrophages in the tumor microenvironment

• Main Authors: Kayla V. Myers, Sarah R. Amend, Kenneth J. Pienta
• Format: Article
• Language: English
• Published: BMC 2019-05-01
• Series: Molecular Cancer
• Subjects: Macrophage; TAM receptors; Tyro3; Axl; MerTK; Efferocytosis
• Online Access: http://link.springer.com/article/10.1186/s12943-019-1022-2

Abstract Tumor-associated macrophages are an abundant cell type in the tumor microenvironment. These macrophages serve as a promising target for treatment of cancer due to their roles in promoting cancer progression and simultaneous immunosuppression. The TAM receptors (Tyro3, Axl and MerTK) are promising therapeutic targets on tumor-associated macrophages. The TAM receptors are a family of receptor tyrosine kinases with shared ligands Gas6 and Protein S that skew macrophage polarization towards a pro-tumor M2-like phenotype. In macrophages, the TAM receptors also promote apoptotic cell clearance, a tumor-promoting process called efferocytosis. The TAM receptors bind the “eat-me” signal phosphatidylserine on apoptotic cell membranes using Gas6 and Protein S as bridging ligands. Post-efferocytosis, macrophages are further polarized to a pro-tumor M2-like phenotype and secrete increased levels of immunosuppressive cytokines. Since M2 polarization and efferocytosis are tumor-promoting processes, the TAM receptors on macrophages serve as exciting targets for cancer therapy. Current TAM receptor-directed therapies in preclinical development and clinical trials may have anti-cancer effects though impacting macrophage phenotype and function in addition to the cancer cells.