Immune checkpoint blockade as a potential therapeutic target: Surveying CNS malignancies

Sarah T. Garber, Yuuri Hashimoto, Shiao-Pei Weathers, Joanne Xiu, Zoran Gatalica, Roel G.W. Verhaak, Shouhao Zhou, Gregory N Fuller, Mustafa Khasraw, John Frederick de Groot, Sandeep K. Reddy, David Spetzler, Amy B Heimberger

Research output: Contribution to journalArticle

56 Scopus citations

Abstract

Background Expression of programmed cell death protein 1 (PD-1)/programmed death ligand 1 (PD-L1) across glioma grades is undocumented, and their interactions with commonly expressed genetic and epigenetic alterations are undefined but nonetheless highly relevant to combinatorial treatments. Methods Patients with CNS malignancies were profiled by Caris Life Sciences from 2009 to 2016. Immunohistochemistry findings for PD-1 on tumor-infiltrating lymphocytes (TIL) and PD-L1 on tumor cells were available for 347 cases. Next-generation sequencing, pyrosequencing, immunohistochemistry, fragment analysis, and fluorescence in situ hybridization were used to determine isocitrate dehydrogenase 1 (IDH1), phosphatase and tensin homolog (PTEN), and tumor protein 53 mutational status, O6-DNA methylguanine-methyltransferase promoter methylation (MGMT-Me) status, PTEN expression, plus epidermal growth factor receptor variant III and 1p/19q codeletion status. Results PD-1+ TIL expression and grade IV gliomas were significantly positively correlated (odds ratio [OR]: 6.363; 95% CI: 1.263, 96.236) - especially in gliosarcomas compared with glioblastoma multiforme (P =. 014). PD-L1 expression was significantly correlated with tumor grade with all PD-L1+ cases (n = 21) being associated with grade IV gliomas. PD-1+ TIL expression and PD-L1 expression were significantly correlated (OR: 5.209; 95% CI: 1.555, 20.144). Mutations of PTEN, tumor protein 53, BRAF, IDH1, and epidermal growth factor receptor or MGMT-Me did not associate with increased intratumoral expression of either PD-1+ TIL or PD-L1 in glioblastoma multiforme even before false discovery rate correction for multiple comparison. Conclusions Targeting immune checkpoints in combination with other therapeutics based on positive biomarker selection will require screening of large patient cohorts.

Original languageEnglish (US)
Pages (from-to)1357-1366
Number of pages10
JournalNeuro-Oncology
Volume18
Issue number10
DOIs
StatePublished - Oct 1 2016

Keywords

  • PD-1
  • PD-L1
  • glioblastoma
  • immune checkpoint
  • low-grade glioma

ASJC Scopus subject areas

  • Oncology
  • Clinical Neurology
  • Cancer Research

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  • Cite this

    Garber, S. T., Hashimoto, Y., Weathers, S-P., Xiu, J., Gatalica, Z., Verhaak, R. G. W., Zhou, S., Fuller, G. N., Khasraw, M., de Groot, J. F., Reddy, S. K., Spetzler, D., & Heimberger, A. B. (2016). Immune checkpoint blockade as a potential therapeutic target: Surveying CNS malignancies. Neuro-Oncology, 18(10), 1357-1366. https://doi.org/10.1093/neuonc/now132