Mechanism and therapeutic potential of microglia regulation in glioblastoma

Glioblastoma (GBM) is the most lethal form of brain cancer in adults. The median survival of GBM patients is only about 14-16 months after initial diagnosis. Genomic profiling has stratified GBM into various subgroups, which are driven by specific genetic alternations of core signaling pathways. However, targeted therapies, such as therapies against receptor tyrosine kinase signaling, have failed in the clinic. Tumor-cell genetic heterogeneity is one of the main reasons for this failure. In contrast, the tumor microenvironment (TME) of GBM is genetically stable, and are considering as the promising therapeutic targets. Tumor-associated microglia and macrophages (TAMs) are the most abundant cell population in the TME, which account for up to 50% of total cells in the GBM tumor mass. Our recent studies have demonstrated that circadian regulator CLOCK/BMAL1 is an oncogene in GBM and highly expressed in glioma stem cells (GSCs), which acts to increase GSC self-renewal through metabolic effects, and recruit microglia into the TME by upregulating chemokine olfactomedin-like 3 (OLFML3) expression (Chen et al., Cancer Discovery, 2020). However, the underlying molecular basis for how OLFML3 triggers microglial infiltration and subsequently how microglia affect immunosuppression and immunotherapy has yet to be determined. Thus, our overall goal in this study is to address this knowledge gap, and in so doing will develop potential therapeutic strategies targeting microglia for treating GBM. To achieve these goals, we propose three specific Aims. In Aim 1, we will identify OLFML3 sensor/receptor or binding protein in microglia, and determine its role in mediating OLFML3-induced microglial infiltration in CLOCK/BMAL1-high GBM. In Aim 2, we will determine the key microglial intracellular pathways that are responsible for OLFML1-induced microglial migration and GBM progression. In Aim 3, we will investigate whether inhibition of microglial infiltration can reverse primary resistance to immunotherapy in GBM, thus developing novel therapeutic strategies combining inhibition of microglia infiltration with immune checkpoint inhibitors. We propose to employ integrated strategies combining gain- and loss-of-function approaches, in vitro and in vivo systems, as well as proteomic and transcriptomic analysis to test each Aim. Together, this project will uncover novel mechanisms for microglial infiltration and reveal new immunotherapeutic strategies for GBM.