Glioblastoma (GBM) is a notoriously immunosuppressive primary brain tumor. The long-term goal of this proposal is to understand the mechanisms of GBM-mediated immunosuppression, identify effective means for reversing immunosuppression, and optimize anti-glioma vaccine therapies. B7-Homologue 1 (B7H1), also known as programmed death ligand 1 (PD-L1), is a cell surface protein that inhibits anti-tumor immunity. It is unique as an immunosuppressive protein because its expression is linked to a fundamental step in oncogenesis: PTEN loss and activation of PI 3-kinase (PI(3)K). This provides potential opportunities for reversal of B7-H1 induction through pharmacological inhibition of the PI(3)K pathway. Another unique feature of B7-H1 is its ability to directly faciliate immunosuppression through multiple mechanisms such as apoptosis of CD8+ T-cells, CD4+ helper T-cells (Thelp) and NK cells, or expansion of immunosuppressive CD4+ regulatory T-cells (Tregs). Expression of B7H1 on circulating monocytes, infiltrating macrophages and resident microglia provides an additional layer of immunoresistance in the tumor microenvironment. Thus, the cell surface expression of B7H1 provides another opportunity to reverse immunosuppression through administration of blocking antibodies against B7H1 or its receptor PD-1. To date, the effects of B7H1 on brain tumor immunity have only been tested using highly passaged glioma cell lines and non-autologous T-cells. Mechanisms of B7H1-mediated immunosuppression have not been fully elucidated. Furthermore, the effects of B7H1 on efficacy of glioma vaccine therapy have not been studied. This proposal seeks to thoroughly characterize the immunosuppressive mechanisms of B7H1 using autologous reagents from GBM patients and animal models of glioma that can be immunologically manipulated. We hypothesize that B7H1 expression in the GBM microenvironment confers immunoresistance that can be effectively reversed by B7H1/PD-1 blockade or pharmacologic inhibition of the PI(3)K pathway. The availability of drugs that inhibit the PI(3)K pathway or block B7-H1 and its receptor PD-1 provides a natural extension of these studies into the realm of patient care.
Glioblastoma (GBM) is an aggressive form of brain tumor for which we have no effective treatment. Immunotherapy offers the hope of highly specific therapy with minimal toxicity, but is limited by local immunoresistance mediated by proteins such as B7 homolog 1 (B7H1). A thorough understanding of B7H1- mediated immunoresistance mechanisms may provide opportunities to augment immunotherapy and extend survival for GBM patients.
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