Mechanism and therapeutic potential of macrophage regulation in glioblastoma

Project: Research project

Project Details

Description

Glioblastoma (GBM) is the most lethal form of brain cancer in adults, with a median survival of one year following diagnosis. Unfortunately, both conventional and targeted therapies have failed to improve GBM patient survival over the last 40 years. Immune cells in the tumor microenvironment (TME) are genetically stable, and have been emerged as promising therapeutic targets. Tumor-associated macrophages/microglia (TAMs) are the most abundant immune cells infiltrating in the GBM TME (accounting for up to 50% of total live cells), where they exhibit an important role in promoting tumor progression and inducing immunotherapy resistance. However, the promise of TAM-targeted therapy or immunotherapy in general has not yet been realized in GBM, due in part to a limited understanding of the molecular mechanisms underlying TAM behavior and function in GBM.
My postdoctoral work in Dr. DePinho’s lab revealed novel molecular mechanisms governing the recruitment of macrophages and microglia into the GBM TME. Notably, I determined that targeting macrophage/microglia infiltration via inhibition of lysyl oxidase (LOX) or circadian regulator CLOCK represents a promising therapeutic approach for GBM (Chen et al., Cancer Cell 2019; Chen at al., Cancer Discovery, 2020). Upon recruitment, macrophages/microglia exhibit a spectrum of phenotypes, including the immunostimulatory M1 phenotype and immunosuppressive M2 phenotype. It is well known that TAMs in GBM are usually polarized toward an M2 phenotype, and reprogramming TAMs from M2 to M1 phenotype could be a promising therapeutic strategy for GBM. My preliminary studies show that TANK binding kinase 1 (TBK1) is uniformly expressed by TAMs in GBM and that this druggable kinase can control macrophage polarization switch between M1 and M2 phenotypes. Mechanically, TBK1 is activated by hypoxia in the GBM TME where HIF1 transcriptionally upregulates TBK1; and TBK1 promotes macrophage M2 polarization via activation of the STK33-IRF7 pathway. Both genetic and pharmacological inhibition of macrophage TBK1 impaired M2 polarization and inhibited GBM progression in multiple GBM mouse models. In summary, these data shows that LOX and CLOCK are responsible for TAM infiltration and TBK1 is essential for TAM M2 polarization in GBM. Since TAMs are immune suppressive cells, the first goal of this project is to determine whether inhibition of TAM infiltration (LOX or CLOCK inhibition) and/or M2 polarization (inhibition of TBK1 and its related signaling pathways) can alter anti-tumor responsiveness to immune checkpoint blockade (ICB). I will also test potential combination therapeutic strategies targeting TAMs and immune checkpoints in GBM mouse models. In addition to regulating immune response, TAMs can also influence tumor progression by producing pro-tumor factors. Therefore, the second goal of this project is to identify the key factors produced by TBK1-regulated M2 TAMs, which contribute to GBM progression. I propose to employ an integrated strategy combining gain- and loss-of-function approaches, in vitro and in vivo systems, as well as proteomic and transcriptomic analysis to identify and characterize these factors. Together, this project will uncover novel mechanisms of GBM progression and offer new therapeutic targets for GBM.
StatusActive
Effective start/end date9/15/208/31/23

Funding

  • National Cancer Institute (4R00CA240896-02)

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