With a two-year survival of less than 20%, malignant gliomas are among the most fatal cancers in humans. Although immunotherapy is being studied as a possible treatment for malignant brain tumors, the immunosuppressive glioma environment has limited the efficacy of this approach. As active mediators of the innate immune response, microglia (MG) and macrophages (MPs) constitute the first line of cellular defense against brain pathogens. Our group and others have shown that the effector function of MG/MPs appears to be suppressed in gliomas through activation of STAT3, yet the exact mechanism by which gliomas induce STAT3 in MG/MPs is unknown. We recently demonstrated that exposure of MG to glioma factors and to low (nM) levels of S100B, a Ca2+binding protein that is highly expressed in astrocytomas, upregulated receptor for advanced glycation end products (RAGE, a S100B receptor), induced STAT3, and inhibited MG proinflammatory function in vitro. Furthermore, blockage of RAGE inhibited STAT3 activity in cultured MG and in MG/MPs in murine gliomas. These findings suggest that the RAGE pathway may play an important role in TAM inactivation and STAT3 induction, and that this process may be mediated through secretion of S100B by glioma cells. Thus, we hypothesize that MG/MP immune function in gliomas is modulated by S100B through engagement of RAGE and inhibition of this pathway may further enhance MG/MP pro-inflammatory function in gliomas. To further study this novel glioma-MG/MP interaction, we will first measure levels of RAGE ligands in i.c. gliomas. Cerebral microdialysis technique will be used to measure intratumoral concentrations of RAGE- activating factors (S100B, S100A8, S100A9, HMGB1, and AGEs) in human gliomas propagated in rodents. These studies will provide important information on S100B and other known RAGE ligands that are secreted in the tumor microenvironment and potentially involved in MG/MP STAT3 activation. In the second aim, we will evaluate the effect of S100B/RAGE inhibition on tumor MP function. RAGE/RAGE ligand interactions will be selectively inhibited and MG/MP immune activation will be studied in murine glioma models. Finally, in the last aim, we will study the molecular mechanisms by which S100B activates STAT3 through the RAGE pathway in tumor MG/MPs. Results from these studies will have significant impact on current treatment of brain tumors as blockage of S100B-RAGE pathway may lead to MG/MP activation and enhancement of immunotherapeutic approaches against diffuse gliomas.
The goal of this five-year project is to study a novel mechanism by which tumor cells inhibit the function of macrophages in gliomas. As components of the immune system, macrophages are equipped with the machinery to rapidly respond to acute changes in the body. For example, they express membrane receptors, such as RAGE, which are activated in response to injury, infection or oxidative stress. In gliomas, however, macrophage function appears to be inhibited. Our recent findings suggest that activation of RAGE by S100B, a protein that is present in most diffuse gliomas, may play a role in this suppression. To better understand this mechanism, we will measure S100B levels (and other factors that bind to RAGE) in glioma models. We will then test if blockage of RAGE and S100B will lead to activation of macrophages in brain tumors. Results from these studies may improve the efficacy of immunotherapies against diffuse gliomas. Furthermore, because macrophages actively participate in other brain pathologies, such as trauma, stroke and inflammation, our findings may be relevant to the treatment of other disease processes.
|Gao, Hang; Zhang, Ian Y; Zhang, Leying et al. (2018) S100B suppression alters polarization of infiltrating myeloid-derived cells in gliomas and inhibits tumor growth. Cancer Lett 439:91-100|
|Keu, Khun Visith; Witney, Timothy H; Yaghoubi, Shahriar et al. (2017) Reporter gene imaging of targeted T cell immunotherapy in recurrent glioma. Sci Transl Med 9:|
|Mirzaei, Hamid R; Rodriguez, Analiz; Shepphird, Jennifer et al. (2017) Chimeric Antigen Receptors T Cell Therapy in Solid Tumor: Challenges and Clinical Applications. Front Immunol 8:1850|
|Ouyang, Mao; White, Ethan E; Ren, Hui et al. (2016) Metronomic Doses of Temozolomide Enhance the Efficacy of Carbon Nanotube CpG Immunotherapy in an Invasive Glioma Model. PLoS One 11:e0148139|
|Brown, Christine E; Alizadeh, Darya; Starr, Renate et al. (2016) Regression of Glioblastoma after Chimeric Antigen Receptor T-Cell Therapy. N Engl J Med 375:2561-9|
|Brown, Christine E; Badie, Behnam; Barish, Michael E et al. (2015) Bioactivity and Safety of IL13R?2-Redirected Chimeric Antigen Receptor CD8+ T Cells in Patients with Recurrent Glioblastoma. Clin Cancer Res 21:4062-72|
|White, Ethan E; Pai, Alex; Weng, Yiming et al. (2015) Functionalized iron oxide nanoparticles for controlling the movement of immune cells. Nanoscale 7:7780-9|
|Carvalho da Fonseca, Anna Carolina; Wang, Huaqing; Fan, Haitao et al. (2014) Increased expression of stress inducible protein 1 in glioma-associated microglia/macrophages. J Neuroimmunol 274:71-7|
|Herrmann, Andreas; Cherryholmes, Gregory; Schroeder, Anne et al. (2014) TLR9 is critical for glioma stem cell maintenance and targeting. Cancer Res 74:5218-28|
|Chen, Xuebo; Zhang, Leying; Zhang, Ian Y et al. (2014) RAGE expression in tumor-associated macrophages promotes angiogenesis in glioma. Cancer Res 74:7285-7297|
Showing the most recent 10 out of 12 publications