Regulatory T-cells (Tregs) are well characterized as a suppressive T-cell population, which act by inhibiting immune responses and preventing potential immunopathologies. Normally they function to maintain peripheral self-tolerance through immunomodulatory cytokines and proteins in order to influence the function of other immune cells. Specifically in various cancer types, a higher than normal population of regulatory T-cells has been well documented at the tumor site as well as systemically. The presence of Tregs has been implicated as a potential mechanism of persistent local and systemic immune suppression. In patients with malignant gliomas, an augmented population of regulatory t-cells is observed in both the peripheral blood and tumor site, which has been hypothesized to contribute to the immunosuppressive environment of gliomas. Currently, the molecular events underlying Treg function in malignant glioma are poorly understood. Recently, we have reported that upregulation of the immunosuppressive B7-H1 molecule is a direct molecular consequence of PTEN deletion, which is a frequent mutation in human malignant gliomas. The relevance of this observation to Treg function in malignant glioma has yet to be fully explored, and other groups have shown a link between B7-H1 protein expression and Treg expansion. We hypothesize that one mechanism by which B7-H1 confers immunoresistance in malignant gliomas is by causing a preferential shift in the T-cell infiltrate towards a Treg predominance. We propose to use specimens taken directly from the operating room to study the impact of B7-H1 expression on T-reg expansion in glioma specimens.
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%. 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 the relationship between B7-H1, an immunosuppressive protein expressed by malignant glioma and regulatory T-cells, a phenotype of T-cell that suppresses immunity.
| 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 |
