Development of Microphage-Directed Immunotherapy for Glioblastoma.
Overview: Glioblastoma (GBM) is the most common primary brain cancer type in humans. GBM is among the most deadly human diseases, currently with a median survival of approximately 14 months, due to its high resistance to conventional chemotherapy and radiotherapy. Immunotherapy holds great promise for GBM treatment. However, current immunotherapy of solid tumors including GBM, primarily by targeting tumor-associated T cells, remains a big challenge, because very few T cells are recruited to the tumors and their activity is low due to local suppressive microenvironment. Notably, macrophages,another type of immune cells, are highly enriched in GBM tumors. Previous research work has shown that tumor-associated macrophages significantly contribute to tumor progression and treatment resistance and the formation of immuno-suppressive microenvironment. Thus, targeting macrophages may represent a promising strategy for GBM immunotherapy. Here, our preliminary studies reveal IL-6 as a new driver for alternative macrophage activation, a way by which macrophages promote tumor progression and inhibit immunity. In this proposal, we plan to use preclinical mouse models to further characterize the in vivo role of IL-6 by genetically disrupting IL-6. More importantly, we will test experimental therapies that combined IL-6 blockade with immune checkpoint inhibition or conventional radio/chemotherapy in GBM treatment. We expect that IL-6 blockade treatment will reduce tumor growth, overcome tumor resistance to radio/chemotherapy, and synergically improve immune checkpoint inhibition. Therefore, targeting IL-6 may offer exciting opportunities for GBM treatment.