A major obstacle to even the best melanoma therapies is that in the majority of cases, the tumor never completely goes away. Even if a little bit remains, called the minimal residual disease, the tumor can eventually start growing again and be drug-resistant. Very little is known about how and why these particular cells manage to survive, so we have taken a comprehensive approach using mouse modeling, human patient samples, and sophisticated genetic analyses to identify what goes on in melanoma residual disease after BRAF inhibition (“BRAFi”). We discovered that a functionally critical immune response to BRAFi starts off strong, but then rapidly recedes, leaving behind the residual tumor cells that somehow evaded or suppressed the immune response. We computationally identified a protein, CXCL9, that decreases at the same time as the immune response and that is predicted to regulate it. Given its known function, we speculate that this “chemokine” primarily recruit T cells into the tumor to aid rejection of the cancer, and that loss of its expression in the tumor over time contributes to the tumor evading the subsequently decreased immune response. We therefore hypothesized that when CXCL9 is forced into the tumors, it would sustain the anti-cancer immune response to further attack the residual cells. Indeed, in a pilot study using our mouse models, we found that injecting CXCL9 into a mouse tumor undergoing BRAFi resulted in the majority of tumors being completely eradicated, and they did not regrow when therapy was stopped.

In this proposal, we further explore CXCL9 therapeutically and mechanistically. First, we will develop a new method of CXCL9 delivery to tumors that should increase its stability: by encapsulating the CXCL9 in small “nanoparticles”, these will protect the protein from degradation long-term, while slowly releasing it into the tumor. This also simplifies the treatment, as these nanoparticles could theoretically be delivered once a week instead of needing daily administration. Second, we will ask which immune cells are recruited to the tumor by CXCL9, and then determine which of the immune cells are most important for carrying out the anti-tumor activity by systematically ablating them from the tumor. This knowledge will help future refinements of CXCL9 as an immunotherapy. The long-term goal of this proposal is to establish CXCL9 as a potential clinical therapy in combination with BRAFi, as a way to target minimal residual disease and prevent tumor relapse in patients.