Glioblastoma is characterized by diffuse infiltration of the brain parenchyma, recurrent growth and an extremely poor prognosis for survival despite aggressive surgical resection, chemotherapy, and radiation. Despite these aforementioned interventions, microscopic tumor remains. Although gliomas are immunogenic, immune-mediated eradication does not occur. Tumor-specific cytotoxic T cells are present within gliomas indicating that the immune system has recognized these tumors. However, we have found that the cytotoxic T cells are inactive in the glioma microenvironment. This functional immune impairment is attributed to a variety of immune suppression mechanisms;however these are associated with the signal transducer and activator of transcription 3 (STAT3) pathway - a key molecular hub of gliomagenesis and tumor-mediated immune suppression. As such, we have developed a novel small molecule inhibitor of STAT3, WP1066, which will be entering clinical trials within the year. During previous funding, we determined the influence of glioma infiltrating microglia on T cells, modulated the activation of T cells in the tumor environment with STAT3 blockade, and tested the therapeutic efficacy of WP1066 in a variety of preclinical murine models of glioma. The renewal application is a natural evolution of our studies and will 1) explore the immunological differences between glioblastoma subtypes that has direct implications for stratification criterion for immunotherapy clinical trials;2) challenging the key paradigm that the immune system inhibits malignant progression but rather may be exerting a selective pressure to enhance immune suppression and malignant transformation/progression;and 3) demonstrating a novel mechanism of how tumor- derived exosomes are modulating innate and adaptive anti-tumor immunity by direct trafficking of pSTAT3 to the nuclear compartment. By further delineating the mechanisms underlying the failure of the immune system to eradicate or suppress gliomas, we hope to improve the efficacy of future immunotherapy, and increase the longevity and quality of life of glioma patients.

Public Health Relevance

This proposal will evaluate the biological and molecular interactions between malignant gliomas and the immune system which has implications for stratification, patient selection, biomarkers and immune therapeutic implementation.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA120813-08
Application #
8663533
Study Section
Special Emphasis Panel (ZRG1-BDCN-W (02))
Program Officer
Muszynski, Karen
Project Start
2006-01-01
Project End
2018-12-31
Budget Start
2014-03-25
Budget End
2014-12-31
Support Year
8
Fiscal Year
2014
Total Cost
$256,952
Indirect Cost
$96,357
Name
University of Texas MD Anderson Cancer Center
Department
Neurosurgery
Type
Other Domestic Higher Education
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
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Bhat, Krishna P L; Balasubramaniyan, Veerakumar; Vaillant, Brian et al. (2013) Mesenchymal differentiation mediated by NF-*B promotes radiation resistance in glioblastoma. Cancer Cell 24:331-46
Dziurzynski, Kristine; Wei, Jun; Qiao, Wei et al. (2011) Glioma-associated cytomegalovirus mediates subversion of the monocyte lineage to a tumor propagating phenotype. Clin Cancer Res 17:4642-9
Wei, Jun; Wu, Adam; Kong, Ling-Yuan et al. (2011) Hypoxia potentiates glioma-mediated immunosuppression. PLoS One 6:e16195

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