The Role of Soluble Axl in Dendritic Cell Regulation within the Tumor Microenvironment

Axl is a receptor tyrosine kinase belonging to the TAM (Tyro3, Axl, and MerTK) family and is widely studied in cancer progression and immune regulation. While Axl signaling in tumor cells has traditionally been viewed as pro-tumorigenic, recent work from the Earp Lab has revealed phenotypes in which tumors in Axl knockout animals exhibit accelerated growth in certain syngeneic models, suggesting that host-derived Axl signaling, in addition to tumor-intrinsic Axl alone, may also play a critical role in shaping the tumor microenvironment (TME).  One potential mechanism underlying this phenomenon is the proteolytic cleavage of membrane-bound Axl, which releases an extracellular domain called soluble Axl (sAxl), into the TME. Because sAxl retains its ligand-binding domain, it may alter the availability and presentation of the Axl ligand Gas6, thereby modulating Axl signaling in immune cells within the TME.  Two competing hypotheses have been proposed to explain sAxl function (Figure 1). In one model, sAxl acts as a decoy receptor that sequesters Gas6, reducing ligand availability and dampening Axl signaling. In the alternative, sAxl stabilizes Gas6 and facilitates ligand delivery, enhancing Axl activation on immune cells.  Therefore, this project will pursue two specific aims:  Aim 1: Determine whether sAxl primarily sequesters Gas6 or facilitates ligand presentation to regulate immune signaling in TME. Aim 2: Define how sAxl influences DC maturation and cytokine signaling in response to tumor-derived cues.