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.
Highlights
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)
There are many central nervous system (CNS)-resident cells including neurons, oligodendrocytes, and astrocytes that when transformed, become neuroblastoma, oligodendroglioma, and astrocytoma. All of these types of tumors are potentially hazardous, here we focus on malignant glioma, with an emphasis of astrocytoma grade IV [ known as glioblastoma multiforme (GBM)], the most common primary adult brain tumor
REGULATORY T CELLS Regulatory T cells, which normally account for only 5–10% of all circulating CD4+ T cells, are classically defined as cells that possess the ability to suppress the proliferation of any cytokine-secreting effector T cell [by down-regulating IL-2 and/or interferon-gamma (IFN-γ) production]
Summary
Hsieh et al (2004), Horwitz et al (2008), Quintana et al (2008) Rubtsov et al (2010), Thornton et al (2010) Bilate and Lafaille (2012), Verhagen et al (2013). In a murine model of colon cancer, the combination of IL12 and CTX eliminates intratumoral Treg and myeloid-derived suppressor cells, while simultaneously inducing pro-inflammatory myeloid cells within the tumor microenvironment, an essential component for facilitating effector T cell infiltration and subsequent tumor rejection (Medina-Echeverz et al, 2011) In support of this approach, PD-1 blockade, low-dose CTX, and combinatorial peptide administration has been shown to synergistically induce a strong antigen-specific immune response by increasing Tc and Tconv infiltration into the malignancy, leading to potent tumor rejection (Mkrtichyan et al, 2011). This approach has shown some promising results, preclinically, this strategy has yet to be tested in the context of patients with cancer
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