Dissecting the Role of AXL in Cancer Immune Escape and Resistance to Immune Checkpoint Inhibition

Abstract

The development and implementation of Immune Checkpoint Inhibitors (ICI) in clinical oncology have significantly improved the survival of a subset of cancer patients with metastatic disease previously considered uniformly lethal. However, the low response rates and the low number of patients with durable clinical responses remain major concerns and underscore the limited understanding of mechanisms regulating anti-tumor immunity and tumor immune resistance. There is an urgent unmet need for novel approaches to enhance the efficacy of ICI in the clinic, and for predictive tools that can accurately predict ICI responders based on the composition of their tumor microenvironment. The receptor tyrosine kinase (RTK) AXL has been associated with poor prognosis in numerous malignancies and the emergence of therapy resistance. AXL is a member of the TYRO3-AXL-MERTK (TAM) kinase family. Upon binding to its ligand GAS6, AXL regulates cell signaling cascades and cellular communication between various components of the tumor microenvironment, including cancer cells, endothelial cells, and immune cells. Converging evidence points to AXL as an attractive molecular target to overcome therapy resistance and immunosuppression, supported by the potential of AXL inhibitors to improve ICI efficacy. Here, we review the current literature on the prominent role of AXL in regulating cancer progression, with particular attention to its effects on anti-tumor immune response and resistance to ICI. We discuss future directions with the aim to understand better the complex role of AXL and TAM receptors in cancer and the potential value of this knowledge and targeted inhibition for the benefit of cancer patients.

Keywords: AXL; EMT; TAM receptors; cell plasticity; immune evasion; immunosuppression; immunotherapy; tumor microenvironment.

Figure 1

GA6/AXL structure and downstream signaling pathways. Ligand binding of the AXL receptor tyrosine kinase promotes autophosphorylation and activates various downstream signaling pathways in a cell- and context-dependent matter, including, but not restricted to p38, NF-kB, PI3K/AKT/mTOR, RAF/MEK/ERK, JAK/STAT/SOCS1/3, SRC/FAK, TWIST, SNAIL and SLUG signaling pathways. These pathways will lead to multiple phenotypes, including proliferation, survival, migration, plasticity, and immune suppression. Ligand-independent mechanisms of AXL activation have been proposed but are not detailed here.

Figure 2

Regulation of AXL expression. Regulation of AXL expression is context-dependent and involves intrinsic and extrinsic factors. Various transcription factors and epigenetic events such as DNA methylation have been identified to regulate AXL expression. AXL protein synthesis is partly regulated by miRNAs. The stabilization of AXL can be affected by ligand binding and interactions with other RTKs. Cleavage of AXL extracellular domain into a soluble form by the action of A Disintegrin And Metalloprotease (ADAM) 7-10. Extrinsic factors, stress, and microenvironmental conditions may also control the different steps. The role of AXL as a sensor of the environmental cues in specific cancer systems and at various stages of cancer progression remains to be fully elucidated.

Figure 3

The multifaceted roles of AXL in the tumor-immune microenvironment. AXL signaling regulates cancer cell-intrinsic properties such as 1) Tumor cell growth and survival, 2) therapy resistance, 3) cancer cell plasticity mediating cancer heterogeneity and 4) increased cell motility. AXL can also mediate cancer cell immune escape through 5) decreased antigen presentation and by 6) resisting immune cell killing. AXL also mediates remodeling of the tumor microenvironment by 7) secretion of immunosuppressive cytokines and chemoattractants, 8) recruitment of immunosuppressive cells, including MDSCs and Tregs, 9) decreased infiltration of activated immune cells including cytotoxic T-cells, and 10) M1 to M2 polarization. Ultimately, this leads to tumor immune evasion and poor prognosis.

Figure 4

Schematic model of AXL-mediated mechanisms of immune escape and the various facets of immunosenzitisation induced by targeting AXL. High AXL expression endows cancer cells with the ability to evade immune-mediated recognition and killing through multiple mechanisms. Cancer cells with active AXL signaling generally express more PD-L1 but less MHC class I molecules, ICAM-1, and NKG2D ligands than cells with inactive or reduced AXL signaling. These characteristics are associated with reduced recognition and elimination by cytotoxic lymphocytes. These cells also secrete an array of cytokines that attract immunosuppressive cell populations or directly inhibit cytotoxic immune cells, further limiting immune responses. Targeting AXL may partially reverse this phenomenon and sensitize carcinoma cells to immune attacks, while amplifying immune responses through the induction of immunogenic cell death.