Glioblastoma multiforme (GBM) is the most common primary brain cancer in adults;in spite of improved standard of care (surgery, chemotherapy, and radiation), less than 5% of the patients survive more than 5 years post-diagnosis. Thus, new treatments for GBM are needed. We and others have shown that immune suppressive cells infiltrate the GBM microenvironment, i.e., regulatory T cells and myeloid derived suppressor cells (MDSC). MDSCs are characterized by co-expression of the myeloid cell-lineage differentiation antigen GR1 and CD11b. Expansion of MDSCs can be triggered by factors produced by the tumor cells themselves, which stimulate myelopoiesis and inhibit the differentiation of mature myeloid cells. Our preliminary data demonstrates that GBM cells in vitro and in vivo express ligands for the receptor for advanced glycation end products (RAGE), i.e., S100 calcium binding protein A8 (S100A8) and S100A9, which have been shown to play a critical role in mediating the expansion of MDSCs in several cancer models. The hypothesis we wish to test is that GBM-derived factors play a major role in activating signaling pathways on MDCS leading to immune suppression and glioma progression. The discovery that GBM-derived ligands play a critical role in brain cancer progression and hamper effective anti-tumor immune responses by promoting the expansion and activation of MDSCs, will lead to a paradigm shift in the development of novel immune therapeutic approaches for GBM aimed at inhibiting MDSCs expansion and activation. The overarching goal of this proposal is to elucidate the role of MDSCs in glioma progression and their impact on the development of novel immune therapeutics. Thus, SA 1 will test the hypothesis that GBM-derived ligands signaling via the RAGE pathway induce the expansion and migration of MDSCs into the tumor microenvironment. In SA2, we will test the hypothesis that glioma-induced MDSCs inhibit anti-tumor effector T cells'functions in vitro and in vivo. In SA3 we will test the hypothesis that blocking the RAGE signaling pathway in vivo will hinder brain tumor progression and enhance T cell mediated anti-GBM immunity. These results will pave the way for novel anti-GBM immune therapeutic strategies aimed at manipulating the expansion and activation of MDSCs;leading to inhibition of tumor progression and enabling the induction of effective anti-tumor immunity in response to immune therapeutics.

Public Health Relevance

Glioblastoma multiforme (GBM) is the most common primary brain cancer in adults;in spite of improved standard of care (surgery, chemotherapy, and radiation), less than 5% of the patients survive more than 5 years post-diagnosis. Immune suppressive cells, i.e., myeloid derived suppressor cells (MDSC;characterized by co-expression of the myeloid cell-lineage differentiation antigen GR1 and CD11b) infiltrate the GBM microenvironment, and could play an important role at inhibiting anti-tumor immunity and facilitating tumor progression. We hypothesize that GBM-derived factors play a major role in activating signaling pathways on MDCS leading to immune suppression and glioma progression, this would lead to a paradigm shift in the development of novel immune therapeutic approaches for GBM aimed at inhibiting MDSCs expansion and activation, thus enabling the induction of effective anti-tumor immunity in response to immune therapeutics.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS074387-03
Application #
8252117
Study Section
Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
Program Officer
Fountain, Jane W
Project Start
2011-04-05
Project End
2016-02-29
Budget Start
2012-03-01
Budget End
2013-02-28
Support Year
3
Fiscal Year
2012
Total Cost
$382,781
Indirect Cost
$135,557
Name
University of Michigan Ann Arbor
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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Lowenstein, Pedro R; Castro, Maria G (2016) Multiple Expressed Endogenous Glioma Epitopes as Novel Vaccines for Gliomas. Clin Cancer Res 22:4760-4762
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Calinescu, Anda-Alexandra; Kamran, Neha; Baker, Gregory et al. (2015) Overview of current immunotherapeutic strategies for glioma. Immunotherapy 7:1073-104
Lowenstein, Pedro R; Castro, Maria G (2015) Glioma trials and viral tribulations: can anything be concluded from non-controlled trials? J Neurol Neurosurg Psychiatry 86:125
Calinescu, Anda-Alexandra; Núñez, Felipe Javier; Koschmann, Carl et al. (2015) Transposon mediated integration of plasmid DNA into the subventricular zone of neonatal mice to generate novel models of glioblastoma. J Vis Exp :

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