Slit-Robo Inhibition to Overcome Immunotherapy Resistance in Melanoma 

Why This Research Matters
Immunotherapy has revolutionized how we treat melanoma, the most aggressive type of skin cancer. These treatments help the body’s immune system find and destroy cancer cells. However, many patients do not respond to these therapies, or their cancer becomes resistant over time. When this happens, treatment options are very limited. Understanding why immunotherapy fails is one of the biggest challenges in melanoma research today. Most research on this topic has focused on T cells, the immune cells that directly kill cancer.

What We Are Studying
In this project, we take a different approach. Instead of focusing only on T cells, we study how the tumor itself creates an environment that prevents the immune system from working properly. We focus on a protein called Slit2, which we believe plays an important role in shutting down the immune response against melanoma. Our previous work shows that Slit2 brings into the tumor other immune cells called macrophages, which can block T cells from working. It also disrupts the lymphatic system – a network that helps immune cells move to lymph nodes, where they are activated to fight cancer. When this system is not working correctly, the immune system cannot properly recognize or attack the tumor.

How the Study Works
We have recently developed new antibodies that can block this pathway. These antibodies are already human and could move quickly into clinical testing. In early studies, blocking this pathway helped “release the brakes” on the immune system and made resistant tumors respond to immunotherapy. In this project, we will study how this pathway controls communication between tumors and the immune system. We will then test whether blocking it using our antibodies can improve responses to immunotherapy in different melanoma models, including advanced disease.

Expected Impact
This research is important because it shifts the focus from the T cells alone to the environment around the tumor. By targeting this newly discovered mechanism, we aim to turn resistant tumors into ones that respond to treatment. Ultimately, this work could lead to new therapies for melanoma patients and improve their survival.