Targeting tregs in malignant brain cancer: Overcoming IDO

Derek A. Wainwright, Mahua Dey, Alan Chang, Maciej S. Lesniak*

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

90 Scopus citations

Abstract

One of the hallmark features of glioblastoma multiforme (GBM), the most common adult primary brain tumor with a very dismal prognosis, is the accumulation of CD4+CD25+Foxp3+ regulatory T cells (Tregs). Regulatory T cells (Tregs) segregate into two primary categories: thymus-derived natural Tregs (nTregs) that develop from the interaction between immature T cells and thymic epithelial stromal cells, and inducible Tregs (iTregs) that arise from the conversion of CD4+FoxP3- T cells into FoxP3 expressing cells. Normally, these Treg subsets complement one another's actions by maintaining tolerance of self-antigens, thereby suppressing autoimmunity, while also enabling effective immune responses toward non-self-antigens, thus promoting infectious protection. However, Tregs have also been shown to be associated with the promotion of pathological outcomes, including cancer. In the setting of GBM, nTregs appear to be primary players that contribute to immunotherapeutic failure, ultimately leading to tumor progression. Several attempts have been made to therapeutically target these cells with variable levels of success. The blood brain barrier-crossing chemotherapeutics, temozolomide, and cyclophosphamide (CTX), vaccination against the Treg transcriptional regulator, FoxP3, as well as mAbs against Treg-associated cell surface molecules CD25, CTLA-4, and GITR are all different therapeutic approaches under investigation. Contributing to the poor success of past approaches is the expression of indoleamine 2,3-dioxygenase 1 (IDO), a tryptophan catabolizing enzyme overexpressed in GBM, and critically involved in regulating tumor-infiltrating Treg levels. Herein, we review the current literature on Tregs in brain cancer, providing a detailed phenotype, causative mechanisms involved in their pathogenesis, and strategies that have been used to target this population, therapeutically.

Original languageEnglish (US)
Article numberarticle 116
JournalFrontiers in immunology
Volume4
Issue numberMAY
DOIs
StatePublished - 2013

Keywords

  • Glioblastoma multiforme
  • IDO (indoleamine 2,3-dioxygenase)
  • Malignant glioma
  • Natural tregs
  • Regulatory T cells
  • Tregs
  • Tumor-induced tregs

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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