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.

Mifamurtide and TAM-like macrophages: effect on proliferation, migration and differentiation of osteosarcoma cells

“…Moreover, in OS, a key osteoblast transcription factor, the Runt Related Transcription Factor 2 (RUNX2), is usually overexpressed [6,7] and metalloprotease MMP-2, alone or with MMP-9, plays a pivotal role in OS metastases and OS patients' outcome [8,9]. Tumor microenvironment (TME) comprises a variety of infiltrating immune cells, including tumor-associated macrophages (TAMs), which are the most abundant [10][11][12][13]. TAMs and their alternative activation states greatly contribute to the progression of tumors [14][15][16][17].…”

PD‐L2+ wound zone macrophage‐like cells display M1/M2‐mixed activation and restrain the effector Th1 responses

“…Macrophages not only reside in stroma but can also sequester in interstitial fluids and transudates . Activated monocytes recruited into the site of inflammation undergo monocyte‐to‐macrophage differentiation; nevertheless, there are no definite and distinctive markers that can be used for differential discrimination of these two cell types . Certain genes such as MERTK, CD64, AXL and TYRO3 have been acknowledged to be macrophage specific; low‐level expression of macrophage‐related markers is generally observed in monocytes as well .…”

Regulation of efferocytosis as a novel cancer therapy

“…Through the PI3K/Akt signaling axis, MerTK induces polarization of M2 macrophages while inhibiting polarization of M1 macrophages, and thereby resulting in the resolution of inflammation [58]. M2 macrophages play a crucial role in the cancer microenvironment by facilitating tumor progression and invasion due to their immunosuppressive characteristics [59]. In addition to innate immunity, MerTK is involved in the modulation in adaptive immunity as genetic ablation of MerTK parallels increased intratumoral CD8 + T lymphocytes and promoted lymphocyte proliferation [48].…”