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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.

SUBMITTER: Myers KV

PROVIDER: S-EPMC6515593 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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

Myers Kayla V KV Amend Sarah R SR Pienta Kenneth J KJ

Molecular cancer 20190514 1

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-tu ...[more]

PMID: 31088471

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Project description:Lung cancer remains a leading cause of cancer death worldwide, with non-small-cell lung cancer (NSCLC) accounting for the majority of cases. Immune checkpoint inhibitors (CPIs), including those targeting programmed cell death protein-1 and its ligand (PD-1/PD-L1), have revolutionized the treatment landscape for various cancers. Notably, PD-1/PD-L1 inhibitor-based regimens now form the standard first-line therapy for metastatic NSCLC, substantially improving patients' overall survival. Despite the progress made using CPI-based therapies in advanced NSCLC, most patients experience disease progression after an initial response due to resistance. Given the currently limited therapeutic options available for second-line and beyond settings in NSCLC, new treatment approaches are needed to improve long-term survival in these patients. Thus, CPI resistance is an emerging concept in cancer treatment and an active area of clinical research.Among the key mechanisms of CPI resistance is the immunosuppressive tumor microenvironment (TME). Effective CPI therapy is based on shifting immune responses against cancer cells, therefore, manipulating the immunosuppressive TME comprises an important strategy to combat CPI resistance. Several aspects of the TME can contribute to treatment resistance in NSCLC, including through the activation of Tyro3, Axl, MerTK (TAM) receptors which are essential pleiotropic regulators of immune homeostasis. Their roles include negatively modulating the immune response, therefore ectopic expression of TAM receptors in the context of cancer can contribute to the immunosuppressive, protumorigenic TME. Furthermore, TAM receptors represent important candidates to simultaneously target both tumor cells and immune cells in the TME. Clinical development of TAM receptor inhibitors (TAM RIs) is increasingly focused on their ability to rescue the antitumor immune response, thereby shifting the immunosuppressive TME to an immunostimulatory TME. There is a strong biological rationale for combining TAM RIs with a CPI to overcome resistance and improve long-term clinical responses in NSCLC. Combinatorial clinical trials of TAM RIs with CPIs are underway with encouraging preliminary results. This review outlines the key mechanisms of CPI resistance, including the role of the immunosuppressive TME, and discusses the rationale for targeting TAM receptors as a novel, promising therapeutic strategy to overcome CPI resistance in NSCLC.

Project description:Inherited photoreceptor degenerations (IPDs) are the most genetically heterogeneous of Mendelian diseases. Many IPDs exhibit substantial phenotypic variability, but the basis is usually unknown. Mutations in MERTK cause recessive IPD phenotypes associated with the RP38 locus. We have identified a murine genetic modifier of Mertk-associated photoreceptor degeneration, the C57BL/6 (B6) allele of which acts as a suppressor. Photoreceptors degenerate rapidly in Mertk-deficient animals homozygous for the 129P2/Ola (129) modifier allele, whereas animals heterozygous for B6 and 129 modifier alleles exhibit an unusual intermixing of degenerating and preserved retinal regions, with females more severely affected than males. Mertk-deficient mice homozygous for the B6 modifier allele display degeneration only in the far periphery, even at 8 months of age, and have improved retinal function compared to animals homozygous for the 129 allele. We genetically mapped the modifier to an approximately 2-megabase critical interval that includes Tyro3, a paralog of Mertk. Tyro3 expression in the outer retina varies with modifier genotype in a manner characteristic of a cis-acting expression quantitative trait locus (eQTL), with the B6 allele conferring an approximately three-fold higher expression level. Loss of Tyro3 function accelerates the pace of photoreceptor degeneration in Mertk knockout mice, and TYRO3 protein is more abundant in the retinal pigment epithelium (RPE) adjacent to preserved central retinal regions of Mertk knockout mice homozygous for the B6 modifier allele. Endogenous human TYRO3 protein co-localizes with nascent photoreceptor outer segment (POS) phagosomes in a primary RPE cell culture assay, and expression of murine Tyro3 in cultured cells stimulates phagocytic ingestion of POS. Our findings demonstrate that Tyro3 gene dosage modulates Mertk-associated retinal degeneration, provide strong evidence for a direct role for TYRO3 in RPE phagocytosis, and suggest that an eQTL can modify a recessive IPD.

Dataset Information

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

Publications

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

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