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

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.

Keywords: Axl; Efferocytosis; M2 macrophage polarization; Macrophage; MerTK; TAM receptors; Tyro3.

Fig. 1

The structure of the TAM receptors and their shared ligands Gas6 and Protein S. a Tyro3, Axl and MerTK share a similar structure of two IgL domains, two FNIII domains and an intracellular TKD. b Gas6 and Protein S contain a Gla domain, four EGF-like domains and two LG-like domains. Abbreviations: IgL = immunoglobulin-like, FNIII = fibronectin type III, TKD = tyrosine kinase domain, Gla = γ-carboxyglutamic acid, EGF = epidermal growth factor, LG-like = laminin G

Fig. 2

TAM receptor signaling skews macrophage polarization. TAM receptor binding and downstream signaling dampens M1 polarization and promotes M2 polarization. Overall, this decreases anti-tumor M1-like phenotypes and functions and increases pro-tumor M2-like phenotypes and functions

Fig. 3

The TAM receptors mediate efferocytosis. The TAM receptors recognize phosphatidylserine (PtdSer) on the outer leaflet of apoptotic cell membranes using Gas6 and Protein S as bridging ligands. Ligand binding promotes TAM receptor dimerization and phosphorylation leading to Vav1-mediated activation of Rho GTPases RhoA, Rac1 and Cdc42. This signaling cascade induces a cytoskeletal rearrangement and phagocytosis of the apoptotic cell

Fig. 4

Nuclear receptors regulate gene transcription post-efferocytosis. PPARs and LXRs form heterodimers with RXRs to regulate gene transcription. Following efferocytosis, lipid components and metabolites from the apoptotic cell bind PPARs and LXRs. These activated nuclear receptors act as transcription factors to upregulate MERTK, AXL and M2-associated gene expression