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 emerging 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 against MDSC infiltration and immune checkpoints in GBM. We propose to employ 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.

The Principal Investigator (PI) Dr. Chen has an extensive experience in tumor immunology field and has a strong ability to perform rigorous and reproducible research in GBM. His primary long-range career objective is to reveal the nature of immune cells (including macrophages and MDSCs) in GBM, and to develop novel immunotherapies for GBM. The second major career objective is to understand the molecular basis underlying the crosstalk among cancer cells, myeloid cells (e.g., MDSCs and macrophages) and adaptive immune system, and to develop novel strategies overcoming immunotherapy resistance in GBM. The proposed studies in this award will reveal the molecular mechanisms for how specific genetic alternation of glioma cells affects MDSC biology and, reciprocally, for how MDSCs contribute to GBM progression and affect the effectiveness of immunotherapies. Moreover, this project shows strong translational potential. For example, we switch our focus from cancer cells to MDSCs in the TME. As a result, we identified galanin (GAL, a neuropeptide) as a potent MDSC chemoattractant in PTEN-deficient GBM. It will be very promising to initial clinical trials using GAL neutralizing antibodies or GAL receptor antagonists in PTEN-deficient GBM patients. Since immune checkpoint inhibitors (ICIs) show minor effect in GBM, and MDSCs are immunosuppressive cells, this project will examine whether the combination therapy with ICIs and inhibition of MDSC infiltration will exhibit synergistic antitumor effect in PTEN-deficient GBM. It has been shown that the risk of GBM is higher in military personnel compared to general population, and GBM is often observed in Veterans who were exposed to Agent Orange. Therefore, the therapy strategies resulted from this award will benefit both active duty Service members and Veterans.