Update on Melanoma Immunotherapy Research Project at Carolinas Medical Center
PURPLE PROMISE FOUNDATION PROJECT: MYELOID-CONDITIONING TO RESTORE IMMUNE POTENCY AGAINST MELANOMA.
OVERALL PROJECT GOALS:
Immunotherapy represents the most effective therapeutic approach currently available to treat late stage melanoma. The underlying mechanism for immunotherapy is dependent on the immune system’s ability to detect tumors and activate anti-tumor immune “effector” cells as a means to promote tumor clearance. Current immunotherapies (e.g. cytokine therapy, immune checkpoint blockade) target relatively late immune events and can produce cancer remission in 10-20% of patients. During the normal pathology of melanoma a subversion of early immune events occurs, leading to an immune bias that allows tumor cells to effectively evade the immune system. A central component to our research is to identify the hallmark(s) of this early immune bias. In doing so, we aim to develop new immunotherapy tools that will restore immune potency against the cancer cells.
Using experimental models of melanoma we have now identified 2 types of immune subversion initiated by the tumor that affect the early immune processes. Specifically, we have identified that this subversion occurs at either a local level, to affect macrophages that infiltrate the tumor per se, or at a non-tumor level where circulating immune (dendritic) cells are affected. Under normal circumstances these immune cells (macrophages and dendritic cells) should promote a potent anti-tumor immune response. However, suppression of their function means that they actually protect the cancer cells against the immune response.
Analysis of macrophages and dendritic cells from models of melanoma demonstrated they express microbial sensors termed Toll-Like Receptors (TLRs). Because of the importance of TLRs in response to microbial infection several synthetic compounds have been developed to activate (agonists) and inhibit (antagonists) their function. Using these compounds with isolated macrophages and dendritic cells, we were able to counteract the suppression of immune function induced by the tumor. We are now in the process of expanding these data to determine whether the changes we observed using isolated cells also occur in experimental animal models.
SPECIFIC GOALS FOR SARAH TEAGUE’S PROJECT:
Sarah Teague, a rising senior from NC State University, was accepted into the Cannon Summer Scholar Program to work with Drs. Foureau and White on the melanoma immunotherapy research project. Her project sought to expand on our preliminary data addressing immune cell subversion by melanoma at the tumor site. In particular, her project aimed to separate the different groups of of macrophages at the tumor site between those termed M1, which act to enhance the immune/inflammatory response, and M2, which are immunosuppressive. To achieve this Sarah first used immunohistochemistry from tumors removed from a mouse model of melanoma to microscopically identify changes in M1/M2 balance. This work was then followed by in vitro analysis of macrophage subtypes using TLR antagonists and a technique termed “flow cytometry”.
Sarah’s work identified M2 macrophages as hallmarks of local immune subversion by melanoma, and that 2 combinations of TLR agonists overcome macrophage subversion and activate pro-inflammatory signals. For her efforts Sarah won the award for best Summer Student Presentation for her talk entitled “Melanoma Immunotherapy: macrophage conditioning to restore immune potency against Melanoma”.