High-dimensional analysis of AXL-mediated immunotherapy resistance: Clinical translation for personalized medicine

Cancer is the leading cause of death in Norway and new treatment concepts are needed. In spite of advances in cancer treatment such as immunotherapy, most patients still do not achieve lasting clinical benefit. Cancer cells acquire therapy resistance, spread and reemerge as advanced malignancy with increased mortality. Our research shows that cancer cells use AXL, a cell surface receptor, to resist therapy and evade the immune system. AXL is broadly associated with cancer, drug resistance and poor clinical outcome. AXL uniquely organizes tumor cells and immune cells to drive therapy failure. Supported by our recent results we seek to better understand the molecular mechanism underpinning how the AXL receptor affects different cells in the tumor. Using state-of-the-art experimental approaches we have identified new AXL receptor configurations with unique cell signaling attributes. The knowledge gained from these studies will be applied to develop new cancer treatment concepts.

Cancer is the leading cause of death in Norway and new treatment concepts are needed. Current cancer treatments such as immunotherapy do not afford lasting clinical benefit. Cancer cells invariably acquire therapy resistance and reemerge as advanced malignancy with increased mortality. Our research shows that cancer cells use the AXL receptor to resist therapy and evade the immune system. AXL is broadly associated with malignancy, drug resistance and poor patient survival and is a critical component of the tumor-immune interface: serving central roles in both tumor cells and immune cells that drive therapy failure. Supported by our recent results we seek to understand the molecular mechanism underpinning how AXL receptor signaling regulates tumor intrinsic resistance to immunotherapy. We address this through a state-of-the-art experimental approach comprising systems-level signal transduction analysis, AXL-targeting in combination with next generation iPS-T cell immunotherapy, and high dimensional single-cell mapping of phenotypic-spatial features of the tumor microenvironment in cancer patient biopsy samples. We will test the following hypotheses: (1) AXL receptor clusters have unique signal transduction characteristics that support therapy resistance; (2) AXL signaling complexes at the tumor-T cell immune synapse block T cell killing of cancer cells; (3) AXL targeting will improve adoptive T cell therapy; (4) AXL complexes at the tumor-T cell interface in cancer patient tumor biopsies will correlate with clinical outcome to immunotherapy. These insights will provide new understanding of a novel molecular mechanism underlying how how cancer evades immunotherapy and elucidate new precision medicine approaches that can address the knowledge gap in cancer treatment necessary to improve patient outcome.