Tumor-associated macrophages are a major component of the innate immune response to cancer. Although macrophages may combat tumor growth through cytokine production, they can paradoxically suppress local immunity as well. In some cancers, tumor associated macrophages can express the cell surface protein B7-H1 (also known as PD-L1). Activated T-cells undergo apoptosis when they come into contact with B7-H1 protein, rendering them ineffective. Malignant glioma is a deadly form of brain tumor that is notoriously immunosuppressive. Several T-cell based immunotherapy protocols have demonstrated impressive peripheral immunological responses, but have been clinically disappointing. We believe the discordance may be due to local immunoresistance, mediated in part by B7-H1+ macrophages found in glioma. To date, this phenomenon and the mechanism of B7-H1 macrophage mediated T-cell apoptosis has not been described in malignant glioma patients. In this proposal, we hypothesize that glioma associated macrophages can suppress local immunity through B7-H1 protein expression and associated induction of T-cell apoptosis. In support of this hypothesis we show that: 1) Macrophages are the predominant immunological cell infiltrating malignant glioma, 2) B7-H1 protein expression is regulated through the PI3Kinase pathway, 3) MCP 1 and MCP 3 which are known to recruit macrophages and activate PI3kinase are expressed at high levels in malignant glioma, and 4) macrophages treated with glioma conditioned media increase B7-H1 protein expression and induce T-cell apoptosis.
Over 17, 000 new cases of central nervous system cancer are diagnosed annually in the United States, accounting for more than 13,000 deaths each year. Primary malignant brain tumors are uniformly fatal, and the 5-year survival rate for the highest grade of malignant glial neoplasm, glioblastoma multiforme (GBM), is less than 2%. Improvements in conventional treatment modalities have provided some extension of survival for patients harboring malignant gliomas. However the therapeutic side effects associated with treatment after surgery are often disastrous. For example, radiation therapy induced necrosis is associated with cognitive impairment caused by focal brain pathology. Neuronal and normal glial cell injury occurs commonly in the brains of long-term survivors after radiation treatment, while the systemic side effects of chemotherapy can be devastating as well. Ultimately, long-term survival precludes a reasonable quality of life. Patients who present with tumor recurrence during or after the administration of conventional therapies are left with few effective treatment options. As a result, experimental therapies such as immunotherapy and gene therapy are being applied to malignant glioma patients with increasing frequency. Immunotherapy is especially appealing because it offers the potential for specifically targeting tumor cells, without injury to normal neural and glial structures. In this proposal we seek to better understand aspects of the tumor micro-environment that contribute to local immunoresistance. Here we will focus on the relationship between expressions of B7- H1, an immunosuppressive protein, on macrophages that infiltrate the tumor. We believe that macrophages expressing B7-H1 protein will cause local T-cell death, and create an immunosuppressive environment.
| Bloch, Orin; Crane, Courtney A; Kaur, Rajwant et al. (2013) Gliomas promote immunosuppression through induction of B7-H1 expression in tumor-associated macrophages. Clin Cancer Res 19:3165-75 |
| Bloch, Orin G; Jian, Brian J; Yang, Isaac et al. (2009) A systematic review of intracranial chondrosarcoma and survival. J Clin Neurosci 16:1547-51 |
