Dissecting the role of CD58 in cancer immune evasion and T cell exclusion

Novel immunotherapies, which unleash the body's own immune system to detect and eliminate melanoma cells, result in exciting responses in some patients, but most patients do not have such a benefit. The underlying reasons for resistance to these therapies is poorly understood. Here, we used patient models that are composed of melanoma cells and also the immune cells from patients with metastatic melanoma. By culturing them in a dish, and using cutting-edge molecular methods (such as genome-editing and single-cell molecular methods), we identified a protein named CD58, which is critical in allowing melanoma cells to escape the immune system, and for melanoma to grow. We now propose to carefully delineate the underlying molecular underpinnings by which melanoma exploits this resistance mechanism. One of the challenges in studying CD58 is the fact that it does not exist in mouse models, which are frequently used to test novel mechanisms and drugs. To overcome this problem, we created mice that harbor both the patient's tumor as well as the patient's immune system. This allowed us to study the mechanisms of resistance mediated by CD58 in a living organism. Furthermore, we have developed two therapies that are specifically designed to enable the patient's immune system to overcome CD58 associated drug resistance. Finally, we use cutting-edge molecular and microscopy methods to demonstrate the relevance of our findings directly in patient blood and tumors. In summary, the proposed work is highly innovative, discovers novel mechanisms of drug resistance and therapies to overcome this resistance, and has the potential to be beneficial for melanoma patients who currently do not experience beneficial responses from other immunotherapies.