Profiling of patients with glioma reveals the dominant immunosuppressive axis is refractory to immune function restoration
Martina Ott, … , Michael A. Curran, Amy B. Heimberger
Martina Ott, … , Michael A. Curran, Amy B. Heimberger
Published July 28, 2020
Citation Information: JCI Insight. 2020;5(17):e134386. https://doi.org/10.1172/jci.insight.134386.
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Research Article Immunology Oncology

Profiling of patients with glioma reveals the dominant immunosuppressive axis is refractory to immune function restoration

Abstract

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. T cells and myeloid cells were isolated from the blood of healthy donors and the blood and tumors from patients with glioma and profiled for the expression of immunomodulatory targets with an available therapeutic. Murine glioma models were used to assess therapeutic efficacy of agents targeting the most frequently expressed immune targets. In patients with glioma, the A2aR/CD73/CD39 pathway was most frequently expressed, followed by the PD-1 pathway. CD73 expression was upregulated on immune cells by 2-hydroxyglutarate in IDH1 mutant glioma patients. In murine glioma models, 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, immune recovery was impaired in the presence of gliomas, indicating that irreversible immune exhaustion limits the effectiveness of adenosine pathway inhibitors in patients with glioma. This study illustrates vetting steps that should be considered before clinical trial implementation for immunotherapy-resistant cancers, including testing an agent’s ability to restore immunological function in the context of intended use.

Authors

Martina Ott, Karl-Heinz Tomaszowski, Anantha Marisetty, Ling-Yuan Kong, Jun Wei, Maya Duna, Katia Blumberg, Xiaorong Ji, Carmen Jacobs, Gregory N. Fuller, Lauren A. Langford, Jason T. Huse, James P. Long, Jian Hu, Shulin Li, Jeffrey S. Weinberg, Sujit S. Prabhu, Raymond Sawaya, Sherise Ferguson, Ganesh Rao, Frederick F. Lang, Michael A. Curran, Amy B. Heimberger

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Figure 5

Targeting A2aR in murine glioma models.

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Targeting A2aR in murine glioma models. (A) A2aR expression was upregula...
(A) A2aR expression was upregulated on CD8+ T cells (P = 0.0046), with a trend in CD4+ T cells (P = 0.077) isolated from the blood of GL261 tumor-bearing mice (n = 6) compared with those in cells from healthy control mice (n = 6). There was no difference in A2aR expression levels in CD11b+ myeloid cells between GL261 tumor-bearing mice (n = 6) and healthy control mice (n = 5) (P = 0.895). P values were calculated using the unpaired 2-tailed t test. (B) Profiling of ex vivo tumor-infiltrating lymphocytes (TILs) demonstrated that both CD4+ and CD8+ T cell populations expressed A2aR (n = 7). (C) A2aR expression level was similar on CD11b+ myeloid cells isolated from GL261 tumor-bearing mice (n = 6) and healthy control mice (n = 5) (P = 0.18). The unpaired 2-tailed t test was used to calculate significance. (D) Survival curve of C57BL/6 mice intracranially implanted with GL261 WT cells and treated with 10 mg/kg SCH58261 (n = 10) or vehicle control (n = 10) for 21 days or until mice showed neurological symptoms of brain tumors. Median survival duration of vehicle control mice was 18.5 days versus 21.5 days with SCH58261 (P = 0.0114). P values were calculated using the log-rank test. (E) Survival curve of Ntv-A mice treated with 10 mg/kg SCH58261 (n = 12) or vehicle control (n = 12) for 21 days. Median survival duration of vehicle control mice was 44.5 days versus 63 days with SCH58261 (P = 0.2292). P values were calculated using the log-rank test. (F) Survival curve of C57BL/6 mice intracranially injected with CD73-overexpressing GL261 cells and treated for 21 days with 60 mg/kg vipadenant (n = 10) or vehicle control (n = 10). Median survival duration of vehicle control mice was 21 days versus 27 days with vipadenant (P = 0.0002). P values were calculated using the log-rank test.