Study Goals: Reveal how a molecule called neuritin supports a population of immune cells that actively interferes with the killing of melanomas; determine if therapies that block neuritin activity can slow or stop tumor growth in mice; and establish if such therapies are likely to improve the effectiveness of current anti-melanoma immunotherapies. Background: For the immune system to function properly, its destructive power must be controlled. Otherwise healthy tissues can be damaged by excessive or self-directed immune responses. Among the mechanisms keeping the immune system in check are so-called “regulatory” T cells (or Tregs). Through their ability to suppress the activity of other immune cells, Tregs restrain the immune system. Unfortunately, Tregs also accumulate in cancer patients and inhibit desirable anti-tumor immune responses. Unexpectedly, we found that Tregs highly express a molecule previously studied in nerves called neuritin. We also showed neuritin to be both important for Treg function and abundantly produced within mouse melanomas. Mice genetically lacking neuritin contained defective Tregs that allow for enhanced resistance to implanted melanomas. While the mechanism responsible for neuritin’s pro-Treg and pro-tumor effects remains unknown, our findings lead us to hypothesize that neuritin promotes the functions of Tregs and therefore can be targeted to improve ant-tumor immunity. Approach: We will examine the effects of neuritin on the function, fitness, and behavior of Tregs and other immune cells. Additionally we will implant melanomas into normal and mutant mice either lacking neuritin or engineered to express excessive amounts of it – revealing the effects of neuritin on tumor size and immune cell composition. Importantly, we will also test the anti-tumor effect of neuritin-blocking antibodies in melanoma-bearing mice. This experimental therapy will also be given in combination with proven immunotherapies to explore the potential for improved anti-tumor effects. Significance & Impact: The nature of neuritin’s suppressive function must be understood before it can be exploited as a therapeutic target. We propose to reveal the elusive mechanism behind neuritin’s function and take the first step in testing the therapeutic value of anti-neuritin antibodies. If successful, these studies will not only conceptually advance our grasp of Treg-mediated suppression in melanoma, they will also justify development and clinical testing of a new immunotherapy weapon. Innovation: We will reveal how neuritin, a completely unappreciated modifier of immune cell activity promotes melanoma growth in mice. We will also, for the first time to our knowledge, test neuritin-blocking therapy as a means to sabotage Tregs and enhance anti-tumor immunity in a preclinical melanoma model. In addition, targeting neuritin to enhance the efficacy of proven immunotherapy.