Purpose: There is a rapidly evolving portfolio of immune therapeutic modulators, but the relative incidence of immune targets in human gliomas is unknown. In order to prioritize available immune therapeutics, immune profiling across glioma grades was conducted followed by preclinical determinations of therapeutic effect in immune competent mice harboring gliomas. Methods: CD4+ and CD8+ T cells and CD11b+ myeloid cells were isolated from the blood of healthy donors and the blood and tumors of newly diagnosed and recurrent glioma patients and profiled for the expression of immune modulatory targets with an available therapeutic. Preclinical murine models of glioma were used to assess therapeutic efficacy of agents targeting the most frequently expressed immune targets. Immune effector function was analyzed in the setting of glioma induced immune suppression. Results: In glioma patients, the adenosine-CD73-CD39 immune suppressive pathway was most frequently expressed, followed by PD-1. CD73 expression was upregulated on immune cells by 2-hydroxygluterate in IDH1 mutant glioma patients. In multiple murine glioma models, including those that express CD73, adenosine receptor inhibitors demonstrated a modest therapeutic response; however, the addition of other inhibitors of the adenosine pathway did not further enhance this therapeutic effect. Although adenosine receptor inhibitors could recover immunological effector functions in T cells after the engagement of this pathway, immune recovery was impaired in the presence of gliomas, indicating that irreversible immune exhaustion limits the effectiveness of inhibitors of the adenosine pathway in glioma patients. Conclusions: This study illustrates vetting steps that should be considered prior to clinical trial implementation for immunotherapy resistant cancers including testing an agents ability to restore immunological function in the context of intended use.
Martina Ott, Karl-Heinz Tomaszowski, Anantha Marisetty, Ling-Yuan Kong, Jun Wei, Maya Duna, Katia Blumberg, Xiaorong Ji, Carmen B Jacobs, Gregory N. Fuller, Lauren A. Langford, Jason T. Huse, James P. Long, Jian Hu, Shulin Li, Jeffrey S. Weinberg, Sujit Prabhu, Raymond Sawaya, Sherise D. Ferguson, Ganesh Rao, Frederick F. Lang, Michael A. Curran, Amy B. Heimberger
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