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.
Highlights
BackgroundCancer is one of the leading causes of death worldwide. In the United States, 1,762,450 new cases and 606,880 cancer-related deaths are estimated to occur in 2019 [1]
The TAM receptor family and their ligands The TAM receptor family is comprised of three receptor tyrosine kinases that share similar structures distinct from other receptor tyrosine kinases (Fig. 1a)
There are multiple alternative names for each in the published literature, and for clarity the names Tyro3, Axl and MerTK will be used throughout this review regardless of the naming convention used in the referenced literature
Summary
Cancer is one of the leading causes of death worldwide. In the United States, 1,762,450 new cases and 606,880 cancer-related deaths are estimated to occur in 2019 [1]. M2 tumor-associated macrophages promote invasion and metastasis of cancer cells through ECM remodeling [14]. Another M2-associated function is phagocytosis of apoptotic cells, i.e., efferocytosis. The TAM receptors (Tyro, Axl and MerTK) are a well-studied family of receptors that, in addition to their function in many other cell types, including cancer cells, play roles in macrophage polarization and efferocytosis. The triple knockout mice developed autoimmune diseases such as rheumatoid arthritis and system lupus erythematosus [18] These phenotypes were found to be due to altered macrophage and dendritic cell function. The role of the TAM receptors on macrophages in different tissues and disease states has been studied. This review will summarize macrophage TAM receptor function in the context of the TME and discuss implications for interventions in cancer therapy
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