Immunologic and gene expression profiles of spontaneous canine oligodendrogliomas

Anna Filley, Mario Henriquez, Tanmoy Bhowmik, Brij Nath Tewari, Xi Rao, Jun Wan, Margaret A. Miller, Yunlong Liu, R. Timothy Bentley, Mahua Dey

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

Malignant glioma (MG), the most common primary brain tumor in adults, is extremely aggressive and uniformly fatal. Several treatment strategies have shown significant preclinical promise in murine models of glioma; however, none have produced meaningful clinical responses in human patients. We hypothesize that introduction of an additional preclinical animal model better approximating the complexity of human MG, particularly in interactions with host immune responses, will bridge the existing gap between these two stages of testing. Here, we characterize the immunologic landscape and gene expression profiles of spontaneous canine glioma and evaluate its potential for serving as such a translational model. RNA in situ hybridization, flowcytometry, and RNA sequencing were used to evaluate immune cell presence and gene expression in healthy and glioma-bearing canines. Similar to human MGs, canine gliomas demonstrated increased intratumoral immune cell infiltration (CD4+, CD8+ and CD4+Foxp3+ T cells). The peripheral blood of glioma-bearing dogs also contained a relatively greater proportion of CD4+Foxp3+ regulatory T cells and plasmacytoid dendritic cells. Tumors were strongly positive for PD-L1 expression and glioma-bearing animals also possessed a greater proportion of immune cells expressing the immune checkpoint receptors CTLA-4 and PD-1. Analysis of differentially expressed genes in our canine populations revealed several genetic changes paralleling those known to occur in human disease. Naturally occurring canine glioma has many characteristics closely resembling human disease, particularly with respect to genetic dysregulation and host immune responses to tumors, supporting its use as a translational model in the preclinical testing of prospective anti-glioma therapies proven successful in murine studies.

Original languageEnglish (US)
Pages (from-to)469-479
Number of pages11
JournalJournal of Neuro-Oncology
Volume137
Issue number3
DOIs
StatePublished - May 1 2018

Keywords

  • Gene expression
  • Glioblastoma
  • Immunotherapy
  • Malignant glioma
  • Spontaneous canine glioma

ASJC Scopus subject areas

  • Oncology
  • Neurology
  • Clinical Neurology
  • Cancer Research

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  • Cite this

    Filley, A., Henriquez, M., Bhowmik, T., Tewari, B. N., Rao, X., Wan, J., Miller, M. A., Liu, Y., Bentley, R. T., & Dey, M. (2018). Immunologic and gene expression profiles of spontaneous canine oligodendrogliomas. Journal of Neuro-Oncology, 137(3), 469-479. https://doi.org/10.1007/s11060-018-2753-4