Mechanism and therapeutic potential of PTEN-regulated MDSCs in glioblastoma

Project: Research project

Project Details

Description

Glioblastoma (GBM) is the most common and lethal form of brain tumor in adults. Genomic profiling has stratified GBM into various subgroups, which are driven by specific genetic alternations of core signaling pathways, including the RTK/RAS/PI3K/PTEN, P53/ARF/MDM2 and RB/CDKN2A pathways. However, targeted therapies, such as therapies against RTK signaling, have failed in the clinic and no effective therapeutic drugs are available to against tumor suppressors. The basis for this failure relates to inter- and intratumoral genetic instability and resultant heterogeneity. Immune cells, such as myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment (TME) are genetically stable, and are emerged as promising therapeutic targets. However, molecular mechanisms for how MDSCs are regulated by glioma cells with specific genetic backgrounds in GBM remain elusive. Here, we hypothesize that genetic alternations of glioma cells can modulate the recruitment of MDSCs into the TME, and blockade of this tumor-MDSC interplay is a powerful means for GBM treatment. The goal of this project is to identify which genetic alternation of glioma cells can drive the infiltration of MDSCs into the GBM TME, and to characterize how MDSCs are recruited into the TME and contribute to GBM progression. Moreover, this project will develop novel combination immunotherapy strategies againsting MDSC infiltration and immune checkpoints in GBM. We propose to employ an integrated strategies combining in vitro and in vivo systems, gain- and loss-of-function approaches as well as proteomic and transcriptomic analyses to test this hypothesis. Together, this project will uncover the molecular mechanisms underlying GBM progression and provide novel therapeutic strategies for GBM under specific genetic backgrounds.
StatusActive
Effective start/end date9/15/219/14/25

Funding

  • U.S. Army Medical Research and Materiel Command (W81XWH2110380)

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