The Role of Tregs in Glioma-Mediated Immunosuppression: Potential Target for Intervention

Abstract

The role of regulatory T cells (Tregs) in mediating immune suppression of anti-tumor immune responses is increasingly becoming appreciated in patients with malignancies -especially within the malignant glioma patient population. This review will discuss the role and prognostic significance of Tregs within glioma patients and will delineate potential approaches for their inhibition that can be used either alone or in combination with other immune therapeutics in clinical trials and in the clinical settings of recurrent and/or residual disease. Keywordsregulatory T cells; glioblastoma multiforme; central nervous system; immunotherapy; vaccine; prognosis Overview of immunosuppressive TregsThe function of the immune system is to recognize foreign materials in the body and distinguish them from normal body tissues and cells. Immune responses consist of cell-mediated (T cells, natural killer cells, and phagocytes) and/or humoral (B cells, antibodies, and complement) responses modified and regulated by cytokines. Antigen-presenting cells (APCs) such as dendritic cells (DCs) and macrophages take up antigens, partially degrade them, and present them to T cells in the context of major histocompatibility complex (MHC) molecules. To fully activate the adaptive immune response, the T cells must receive two signals: one through the T cell receptor and the other through the co-stimulatory receptor CD28, which recognizes the co-stimulatory molecules CD80 and CD86 expressed on the surface of APCs. Failure to do so Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptNeurosurg Clin N Am. Author manuscript; available in PMC 2011 January 1. Although the mechanism by which nTregs exert their effects on the effector T cells has yet to be fully elucidated [31][32][33][34], it likely results from downregulation of IL-2 cytokine production and may involve membrane-bound cytotoxic T lymphocyte antigen-4 (CTLA-4), a negative regulator of T cell activation, a member of the CD28/B7 immunoglobulin superfamily that is constitutively expressed on Tregs [35], and whose expression is up-regulated in activated T cells [36,37]. . The development of nTregs is regulated by the Foxp3 gene in CD4 + /CD25 + T cells [38]. The primary role of nTregs is suspected to be maintenance of a constant homeostatic balance by curtailing the effects of autoreactive T cells in noninflammatory settings [32].Tregs in circulating peripheral blood include not only nTregs differentiated in the thymus but also Foxp3 + Tregs generated extrathymically by the conversion of naïve T cells via chro...

Autologous T-cell Therapy for Cytomegalovirus as a Consolidative Treatment for Recurrent Glioblastoma

“…In addition, these T cells showed increased expression of checkpoint inhibitory receptors when compared with the circulating effector cells from peripheral blood, potentially reflecting the impact of the tumor microenvironment. We further detected higher amounts of regulatory T cells, which might contribute to immunosuppression in GBM tissues (43). These observations were supported by gene expression analysis of antigen-specific T cells used for adoptive immunotherapy.…”

Phase II Study of Aflibercept in Recurrent Malignant Glioma: A North American Brain Tumor Consortium Study

“…T lymphocytes are thought to infiltrate gliomas at an early stage 29 in which they mediate immunosuppression and resistance to treatment. 29,30 CXCR4 is also expressed on macrophages, granulocytes, and myeloid suppressor cells.…”

Immunosuppressive Myeloid Cells’ Blockade in the Glioma Microenvironment Enhances the Efficacy of Immune-Stimulatory Gene Therapy

“…18,19 Gliomas have been shown to employ a variety of mechanisms to suppress the immune system, such as downregulation of MHC class I molecules, production of transforming growth factor-b (TGF-b), vascular endothelial growth factor (VEGF), prostaglandin E2, and IL-10, expression of ligands of checkpoint receptors, such as PD-1, and accumulation of immunosuppressive cells, such as myeloidderived suppressor cells (MDSCs), regulatory T cells (Tregs), and tumor-associated macrophages (TAMs). [23][24][25][26][27][28][29][30] It has been previously shown in human samples and experimental GBM models that MDSCs are powerful inhibitors of anti-tumor immune responses. 30,31 Through a variety of mechanisms that inhibit T cell activation and expansion, including the production of arginase and inducible nitric oxide synthase (iNOS), reactive oxygen species and/or reactive nitrogen species (ROS and/or RNS), release of IL-10, expansion of regulatory T cells (Tregs), and inhibition of T cell migration, MDSCs have been shown to promote immunosuppression and tumor progression.…”