Abstract
Extensive interest in cancer immunotherapy is reported according to the clinical importance of CTLA-4 and (PD-1/PD-L1) [programmed death (PD) and programmed death-ligand (PD-L1)] in immune checkpoint therapies. AXL is a receptor tyrosine kinase expressed in different types of cancer and in relation to resistance against various anticancer therapeutics due to poor clinical prognosis. AXL and its ligand, i.e., growth arrest-specific 6 (GAS6) proteins, are expressed on many cancer cells, and the GAS6/AXL pathway is reported to promote cancer cell proliferation, survival, migration, invasion, angiogenesis, and immune evasion. AXL is an attractive and novel therapeutic target for impairing tumor progression from immune cell contracts in the tumor microenvironment. The GAS6/AXL pathway is also of interest immunologically because it targets fewer antitumor immune responses. In effect, several targeted therapies are selective and nonselective for AXL, which are in preclinical and clinical development in multiple cancer types. Therefore, this review focuses on the role of the GAS6/AXL signaling pathway in triggering the immunosuppressive tumor microenvironment as immune evasion. This includes regulating its composition and activating T-cell exclusion with the immune-suppressive activity of regulatory T cells, which is related to one of the hallmarks of cancer survival. Finally, this article discusses the GAS6/AXL signaling pathway in the context of several immune responses such as NK cell activation, apoptosis, and tumor-specific immunity, especially PD-1/PDL-1 signaling.
Highlights
Extensive interest in cancer immunotherapy is reported according to the clinical importance of CTLA-4 and (PD-1/programmed death ligand-1 (PD-L1)) [programmed death (PD) and programmed death-ligand (PD-L1)] in immune checkpoint therapies
Tumor cells may induce the expression of AXL and growth arrest-specific 6 (GAS6) in monocytic myeloidderived suppressor cells (M-MDSCs) and polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) [20]
It was demonstrated that osteoblast-derived GAS6 induces AXL expression in tumor cells [34], which suggests that paracrine GAS6/AXL signaling promotes survival, inhibits apoptosis, and mediates homing of tumor cells to the bone
Summary
Edited by: Diana Boraschi, Shenzhen Institutes of Advanced Technology (CAS), China. Reviewed by: Douglas Graham, Emory University, United States Carlo Cenciarelli, National Research Council (CNR), Italy. AXL and its ligand, i.e., growth arrest-specific 6 (GAS6) proteins, are expressed on many cancer cells, and the GAS6/AXL pathway is reported to promote cancer cell proliferation, survival, migration, invasion, angiogenesis, and immune evasion. This review focuses on the role of the GAS6/AXL signaling pathway in triggering the immunosuppressive tumor microenvironment as immune evasion. This includes regulating its composition and activating T-cell exclusion with the immunesuppressive activity of regulatory T cells, which is related to one of the hallmarks of cancer survival. The tumor microenvironment can regulate AXL expression in various cells, and AXL seems to have a potential role in tumor development, progression, and metastasis
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