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 #
5R01CA120813-12
Application #
9402057
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Welch, Anthony R
Project Start
2006-01-01
Project End
2018-12-31
Budget Start
2018-01-01
Budget End
2018-12-31
Support Year
12
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Neurosurgery
Type
Hospitals
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
Shingu, Takashi; Ho, Allen L; Yuan, Liang et al. (2017) Qki deficiency maintains stemness of glioma stem cells in suboptimal environment by downregulating endolysosomal degradation. Nat Genet 49:75-86
Wang, Qianghu; Hu, Baoli; Hu, Xin et al. (2017) Tumor Evolution of Glioma-Intrinsic Gene Expression Subtypes Associates with Immunological Changes in the Microenvironment. Cancer Cell 32:42-56.e6
Hodges, Tiffany R; Ott, Martina; Xiu, Joanne et al. (2017) Mutational burden, immune checkpoint expression, and mismatch repair in glioma: implications for immune checkpoint immunotherapy. Neuro Oncol 19:1047-1057
Ling, Hui; Pickard, Karen; Ivan, Cristina et al. (2016) The clinical and biological significance of MIR-224 expression in colorectal cancer metastasis. Gut 65:977-989
Ferguson, Sherise D; Xiu, Joanne; Weathers, Shiao-Pei et al. (2016) GBM-associated mutations and altered protein expression are more common in young patients. Oncotarget 7:69466-69478
Garber, Sarah T; Hashimoto, Yuuri; Weathers, Shiao-Pei et al. (2016) Immune checkpoint blockade as a potential therapeutic target: surveying CNS malignancies. Neuro Oncol 18:1357-66
Zhao, Hua; Heimberger, Amy B; Lu, Zhimin et al. (2016) Metabolomics profiling in plasma samples from glioma patients correlates with tumor phenotypes. Oncotarget 7:20486-95
Kong, Ling-Yuan; Wei, Jun; Fuller, Gregory N et al. (2016) Tipping a favorable CNS intratumoral immune response using immune stimulation combined with inhibition of tumor-mediated immune suppression. Oncoimmunology 5:e1117739
Gabrusiewicz, Konrad; Rodriguez, Benjamin; Wei, Jun et al. (2016) Glioblastoma-infiltrated innate immune cells resemble M0 macrophage phenotype. JCI Insight 1:
Nduom, Edjah K; Wei, Jun; Yaghi, Nasser K et al. (2016) PD-L1 expression and prognostic impact in glioblastoma. Neuro Oncol 18:195-205

Showing the most recent 10 out of 46 publications