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.
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.
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