Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor in adults; median survival from diagnosis is ~15-21 months. Anti-GBM immune strategies constitute novel and exciting therapeutic adjuvants to improve survival due to surgery, chemo- and radiotherapy. However, it has been challenging to develop effective anti-GBM immune responses that translate into increased patients' survival. As systemic immune responses against GBM antigens can be induced, clinical failure is thought to be due to powerful GBM induced immune suppression. Immune suppression in GBM patients is mediated by various mechanisms that include immature myeloid cells (IMCs) that accumulate in the tumor microenvironment. Subtypes of immature myeloid cells are: (i) myeloid derived suppressor cells (MDSCs), (ii) immunosuppressive tumor associated macrophages (TAMs), and, (iii) Tie2+ monocytes (TEMs). GBMs recruit immature myeloid cells to the tumor microenvironment where they inhibit anti-tumor immune responses, for example, by directly inhibiting T-cell effector function. Additional immune suppressive mechanisms involve: accumulation of Tregs, immunosuppressive molecules (i.e., indoleamine2, 3-dioxygenase 1 (IDO), cytotoxic T-lymphocyte antigen 4 (CTLA4), and programmed death 1 receptor ligand (PDL1), and cytokines, (i.e., IL10, TGF?). To identify secreted factors which attract immune-suppressive IMCs into the GBM microenvironment we performed DNA microarray analysis on endogenous and transplantable mouse and human GBM cells and identified CXCL12 as a possible candidate. We also identified CXCR4, the cognate CXCL12 receptor, on immature myeloid cells within the GBM microenvironment supporting the hypothesis that CXCL12/CXCR4 plays an important role in attracting IMCs to the GBM microenvironment. To ascertain the role played by CXCL12-CXCR4 signaling in GBM progression and in regulating anti-GBM immune therapies, we propose to use an immune competent, genetically engineered endogenous mouse GBM model. Intracranial tumors are induced by Sleeping Beauty (SB)-mediated insertion of genetic alterations found in human GBM. Preliminary data show that conditioned media from both transplantable and SB-induced GBM elicit a high level of IMCs' expansion in vitro. In GBM models in vivo, we observed accumulation of IMCs within the GBM microenvironment and in the peripheral circulation. CXCR4 blockade significantly prolonged median survival of mice bearing endogenous GBM. We will use CXCL12 and/or CXCR4 gene ablation models to test the hypothesis that CXCL12-CXCR4 signaling axis plays a major role in determining the immune profile, both qualitatively and quantitatively, of the GBM microenvironment and thus has profound effects on disease progression. We further hypothesize that blocking accumulation of IMCs in combination with anti-GBM immune stimulatory strategies will provide a powerful adjuvant approach to treat malignant brain cancer.
Glioblastoma multiforme (GBM) is the most prevalent malignant primary brain cancer in adults, characterized by the presence of a high percentage of immune suppressive immature myeloid cells (IMCs) which inhibit anti-GBM T-cells' functions mediating tumor invasion and disease progression. This project aims to elucidate the role played by CXCR4-CXCL12 signaling in the GBM microenvironment in mediating the accumulation of IMCs, facilitating tumor invasion and disease progression. We hypothesize that CXCR4 blockade will enhance the efficacy of anti- GBM immunotherapies and will uncover a novel therapeutic target for this devastating cancer.
Showing the most recent 10 out of 21 publications
