IDO Expression in Brain Tumors Increases the Recruitment of Regulatory T Cells and Negatively Impacts Survival

Abstract

Purpose Glioblastoma multiforme (GBM) is an aggressive adult brain tumor with a poor prognosis. One hallmark of GBM is the accumulation of immunosuppressive and tumor-promoting CD4+FoxP3+GITR+ regulatory T cells (Tregs). Here, we investigated the role of indoleamine 2,3 dioxygenase (IDO) in brain tumors and the impact on Treg recruitment. Experimental Design To determine the clinical relevance of IDO expression in brain tumors, we first correlated patient survival to the level of IDO expression from resected glioma specimens. We also used novel orthotopic and transgenic models of glioma to study how IDO affects Tregs. The impact of tumor-derived and peripheral IDO expression on Treg recruitment, GITR expression and long-term survival was determined. Results Downregulated IDO expression in glioma predicted a significantly better prognosis in patients. Co-incidently, both IDO -competent and -deficient mice showed a survival advantage bearing IDO-deficient brain tumors, when compared to IDO-competent brain tumors. Moreover, IDO-deficiency was associated with a significant decrease in brain-resident Tregs, both in orthotopic and transgenic mouse glioma models. IDO-deficiency was also associated with lower GITR expression levels on Tregs. Interestingly, the long-term survival advantage conferred by IDO-deficiency was lost in T cell-deficient mice. Conclusions These clinical and pre-clinical data confirm that IDO expression increases the recruitment of immunosuppressive Tregs which leads to tumor outgrowth. In contrast, IDO deficiency decreases Treg recruitment and enhances T cell-mediated tumor rejection. Thus, the data suggest a critical role for IDO-mediated immunosuppression in glioma and supports the continued investigation of IDO-Treg interactions in the context of brain tumors.

Circulating T regulatory cells migration and phenotype in glioblastoma patients: an in vitro study

“…Data regarding phenotypic and functional analysis of circulating Treg further suggest that this immunosuppressive subpopulation display similar characteristics in GBM patients and in healthy controls [4]. Among the molecules studied, GITR upregulation in GBM-infiltrating lymphocytes has been reported to be particularly pronounced on infiltrating Treg [34]. In our patients, expression of GITR on circulating Treg was almost doubled compared to healthy controls; however, due to the high variability observed in patients, this increase was not statistically significant.…”

In vivo metabolism of tryptophan in meningiomas is mediated by indoleamine 2,3-dioxygenase 1

“…19 A recent study has also shown that this mechanism is operative in malignant gliomas where high IDO expression is associated with recruitment of regulatory T cells and adversely affects survival. 44 For the first time, we demonstrate that meningiomas express IDO in vivo and lose this expression when the tumor cells are dissociated and placed into culture. However, IDO expression can be effectively reinduced following exposure to IFNγ.…”

Effects of tumor grade and dexamethasone on myeloid cells in patients with glioma

“…This model is supported by the various redundant mechanisms of immunosuppression in the TME, including soluble GBM tumor cell derived factors such as TGFβ, 66 LDH5, 5 IL-10, 67 and IDO. 68 Surface proteins including PD-L1, 69 and decreased MHC Class I expression on tumor cells 70 that likely influence TAM phenotypes and functions independently of CD163 expression are found in GBM, but not in the tumors of patients with low-grade gliomas.…”