Immune Evasion Mechanism and AXL

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.

Single-cell transcriptome reveals cellular hierarchies and guides p-EMT-targeted trial in skull base chordoma

“…S4b ) 24 . One of the highly expressed genes in infiltrated myeloid DCs was AXL , a key PD-L1 protein regulator capable of increasing PD-L1 protein expression 25 – 27 . As reported, DCs could potentially interact with multiple T-cell subsets via PD-1/PD-L1, leading us to compare the expression of PD-1/PD-L1 and its regulators in all immune cells 28 .…”

The Fairy Chemical Imidazole-4-carboxamide Inhibits the Expression of Axl, PD-L1, and PD-L2 and Improves Response to Cisplatin in Melanoma

“…However, excessive activation of Axl exerts detrimental effects in cancer. Stimulation of the Axl receptor tyrosine kinase leads to activation of the intracellular Akt signaling pathway that promotes cell survival and growth in tumors by suppressing pro-apoptotic proteins [15,16,56]. Axl kinase activation also inhibits the immune response in the tumor microenvironment by promoting the secretion of immunosuppressive cytokines, the secretion of PD-L1 and PD-L2, the infiltration of myeloid-derived suppressor cells, and the inhibition of T cells [17,56].…”

“…Stimulation of the Axl receptor tyrosine kinase leads to activation of the intracellular Akt signaling pathway that promotes cell survival and growth in tumors by suppressing pro-apoptotic proteins [15,16,56]. Axl kinase activation also inhibits the immune response in the tumor microenvironment by promoting the secretion of immunosuppressive cytokines, the secretion of PD-L1 and PD-L2, the infiltration of myeloid-derived suppressor cells, and the inhibition of T cells [17,56]. The effects of Axl kinase have been linked to enhanced tumor cell dissemination, resistance to anticancer therapy, and poor prognosis in patients with malignancy [57].…”

Identification of Ferroptosis-Related Prognostic Signature and Subtypes Related to the Immune Microenvironment for Breast Cancer Patients Receiving Neoadjuvant Chemotherapy

“…Extensive interest in cancer immunotherapy is reported according to the clinical importance of CTLA-4 and PD-1/PD-L1 in immune checkpoint therapies ( 48 ). The main immune checkpoints for breast cancer include CTLA-4, PD-1/PD-L1, lymphocyte activation gene 3 (LAG-3), T-cell immunoglobulin domain and mucin 3 (TIM-3), and other molecules ( 49 ).…”