MCB Assistant Professor of Immunology and Pathogenesis, Michel DuPage, is the recipient of a Hope with Hazel St. Baldrick's Scholar grant. His funded project aims to target regulatory T cells (Tregs) as a novel method to enhance immune responses to Neuroblastoma (NB) - the third most common form of childhood cancer, and the leading cause of cancer deaths in children 1-4 years of age.
They will investigate the role of Tregs and the capacity to target them by modulating the function of the epiginetic regulator Enhancer of Zeste Homolog 2 (EZH2) to simultaneously target neoplastic cells and Tregs as a novel method to enhance immune responses to NB.
Background: The recent success of immune-based cancer therapies is revolutionizing the treatment of cancer. However, it is already apparent that out latest arsenal of immune-boosting drugs, namely checkpoint blockade immunotherapy, will not benefit all patients, and in particular, children suffering from cancer. The distinct etiology of most pediatric cancers, as compared to adult forms, likely contributes to this glaring lack of efficacy, and implies that new rules must be learned to effectively investigate immune responses to pediatric cancers. Most significantly, pediatric tumors develop early in life while the immune system is still being educated, allowing tumors to co-opt natural mechanisms that promote immune tolerance to "self" as a means to escape immune regulation.
Tregs are a subset of immunosuppressive CD4+ T cells that play an essential role in preventing autoimmunity to "self" but are also found in most tumors where they dampen anti-tumor immune responses.
Most recently, the DuPage lab discovered a superior mechanism to selectively target Tregs in cancer by disruption of EZH2. This reprograms Treg functionality specifically in tumors, converting them from an immunosuppressive to pro-inflamatory phenotype that enhances anti-tumor immune responses. In NB, EZH2 function within the neoplastic cells was recently shown to promote cancer intrinsically. Therefore, a unique opportunity exists whereby pharmacological inhibition of EZH2 function in children with NB will target cancer cells directly while simultaneously altering Treg function to enhance cancer immunity.
Photo Credit: Mark Hanson of Mark Joseph Studios.