Immune therapies termed “immune checkpoint inhibitors” remove key “brakes” on immune cells. These treatments lead to long-term responses and cures in some patients with melanoma, but may also cause severe side effects. These toxicities result from abnormal immune cell activation, and are highly unpredictable. This presents several important obstacles to improving melanoma treatment: 1) We are unable to predict which patients will develop severe toxicities; 2) More aggressive treatment combinations cause more toxicity, limiting our ability to develop more active combinations; and 3) Patients who have long-term benefit may still develop devastating side effects. To address these problems, we propose to perform an in-depth study of the most common severe toxicity: colitis (inflammation of the colon). To do this, we plan the following aims. First, we will look at genetic and immune factors that may predispose patients to colitis. Many autoimmune conditions, that have similarities with immune colitis, have such genetic and immune system links. Second, we will take colon biopsies from patients who have colitis, and perform in-depth analysis of these tissues. We will compare the specific immune cells between the colon, blood, and tumor to better understand how the immune system is working in all three areas, and how to “turn off” abnormal activation while maintaining activity against the tumor. Third, we will collect cases from large melanoma centers to determine exactly when and how colitis occurs, and how best to treat it. Ultimately, we propose that in-depth study of this common and severe toxicity will allow us to understand it, prevent it, and treat it more effectively.