Local immunoresistance and systemic immunosuppression represent major impediments to effective immunotherapy for gliomas. The immune response to vaccination is largely dependent on tumor specific CD8+ cytolytic T cells, and can be suppressed by induction of T cell apoptosis. B7-Homologue 1 (B7-H1) is a surface protein on glioma cells that binds to the programmed death 1 (PD-1) receptor on T cells and can induce anergy or apoptosis. Tumor-associated macrophages are thought to contribute to the local immune response through antigen presentation and the release of specific cytokines. Recent evidence suggests that macrophages can be polarized to pro-inflammatory (M1) or anti-inflammatory (M2) phenotypes, defined by their cascade of cytokines. In addition, this evidence demonstrates that tumor-associated macrophages can express B7-H1 at the cell surface and can induce apoptosis of activated T cells, independent of glioma cells. Macrophage- mediated suppression of the cytolytic T cell response may be a primary factor in the local and systemic immunoresistance seen in glioma patients. We will provide preliminary evidence that 1) B7-H1 expression on macrophages is increased in peripheral blood and tumor from glioblastoma patients, 2) glioma cells can stimulate B7-H1 expression in peripheral monocytes through a soluble factor, 3) B7-H1 expressing monocytes induce CTL apoptosis, 4) glioma cells stimulate monocytes to produce IL-10, and 5) IL-10 is sufficient to activate B7-H1 expression in monocytes. Based on these data, we hypothesize that tumor-derived soluble factors from gliomas induce IL-10 production in tumor-associated macrophages, which activates B7- H1 expression through autocrine signaling. In this proposal we will evaluate the spatiotemporal distribution of B7-H1 on tumor-associated macrophages relative to tumor burden and investigate the mechanisms by which B7-H1 expression is induced. Specifically, we will study the role of IL-10 autocrine signaling and activation of the STAT3 pathway to evaluate their involvement in this process. We will also take an unbiased protein purification approach to identify the glioma-derived factor responsible for upregulation of B7-H1 on monocytes.

Public Health Relevance

Glioblastoma (GBM) is a terminal diagnosis with poor survival despite current standard of care therapies. Much effort and emphasis has been placed on developing immunotherapy for the treatment of GBM; however, local tumor immunoresistance and systemic immunosuppression have limited the clinical efficacy of vaccine therapies. Tumor-associated macrophages have been shown to exert an immunosuppressive effect in glioma through the release of anti-inflammatory cytokines. We now describe a newly understood mechanism of immunoresistance in macrophages, surface expression of B7-H1, and propose innovative strategies to identify the glioma-derived factor that induces expression. This work promises to identify new targets for intervention to limit glioma-induced immunosuppression and increase the efficacy of immunotherapy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Transition Award (R00)
Project #
5R00NS078055-05
Application #
9120946
Study Section
Special Emphasis Panel (NSS)
Program Officer
Fountain, Jane W
Project Start
2014-08-01
Project End
2017-07-31
Budget Start
2016-08-01
Budget End
2017-07-31
Support Year
5
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Northwestern University at Chicago
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
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Lamano, Jonathan B; Ampie, Leonel; Choy, Winward et al. (2016) Immunomonitoring in glioma immunotherapy: current status and future perspectives. J Neurooncol 127:1-13
Ampie, Leonel; Choy, Winward; Lamano, Jonathan B et al. (2015) Heat shock protein vaccines against glioblastoma: from bench to bedside. J Neurooncol 123:441-8