Our goal of this application is to test the hypothesis that blocking the newly identified immune suppressive regulator fibrinogen-like protein 2 (Fgl2) in GBM will comprehensively reverse tumor-mediated immune suppression thereby allowing immunological clearance of gliomas within the central nervous system. We have discovered that Fgl2 is highly expressed in GBM tissues(recently published by JNCI). Patients with GBM tumors that have high levels of Fgl2 expression have a statistically shorter overall survival time relative to those with low expression levels. As further proof of concept, Fgl2-engineered GBM tumors progressed rapidly with neurological sequela and death when compared to the reporter gene-GFP-engineered GBM cells in syngeneic mice. Our data shows that Fgl2 is a key immune suppressive hub that correlates with immune checkpoint family expression (PD-L1, PD-1, and CTLA-4), immune suppressive cytokines (TGF-?), and glioma-infiltrating, of immunosuppressive immune populations such as myeloid-derived suppressor cells (MDSCs), Tregs and M2 macrophages. One underlying mechanism for this observation is Fgl2 induced CD39 and CD73 in T cells. The CD39 protein converts ATP to ADP and AMP, which is then converted to adenosine by CD73. Adenosine is an immunosuppressive metabolite that then suppresses T lymphocyte activation and effector function. Furthermore, the CD39/CD73 complex enhances the conversion of M1 into tumor-promoting M2 to promote tumor growth. Based on these data, we have created a first generation antibody that blocks Fgl2 immune suppressive activity and increases median survival in murine models with established intracerebral gliomas. To test our central hypothesis for this application, the following aims are proposed:
Aim 1 : Determine the association of Fgl2 expression with immune suppression in human GBM and investigate the mechanism of CD39/CD73 expression in different types of immune cells in GBM;
Aim 2 : Select the most therapeutically efficacious cross-species Fgl2 mAb that promotes antitumor immune response. Impact: This study will yield a therapeutic candidate ? a Fgl2 blocking antibody that may reverse tumor- mediated immune suppression and the number of immune suppressive cells in GBM. Considering that Fgl2 can be detected in almost all GBMs, with most having very high levels, such a candidate therapeutic will be important. This study will also further mechanistically elucidate how Fgl2 regulates immune suppressive gene expression in immune suppressive cells and within effector immune populations. Finally, this study will show whether detection of Fgl2 in circulating GBM tumor cells (CTC) using our newly invented universal CTC capture technology (PCT/US2014/020615) will correlate with the level of GBM tumor Fgl2 expression as a biomarker for guiding blocking therapy in the future. This type of assay would also be highly significant as a longitudinal liquid biopsy for gene expression analysis that could be used in the context of multiple clinical applications such as early progression/treatment failure and response to treatment.
Our goal of this application is to select an immune suppressive blocker to boost the immune surveillance against GBM and boost the effect of chemotherapy. Such a study is highly relevance to human health.
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