Infiltrating T Cells Increase IDO1 Expression in Glioblastoma and Contribute to Decreased Patient Survival

Abstract

Purpose Indoleamine 2,3 dioxygenase 1 (IDO1) mediates potent immunosuppression in multiple preclinical models of cancer. However, the basis for elevated IDO1 expression in human cancer, including the most common primary malignant brain tumor in adults, glioblastoma (GBM), is poorly understood. The major objective of this study is to address this gap in our understanding of how IDO1 expression contributes to the biology of GBM, and whether its level of expression is a determinant of GBM patient outcome. Experimental Design Patient-resected GBM, the cancer genome atlas, human T cell:GBM co-cultures, as well as nu/nu, NOD-scid and humanized (NSG-SGM3-BLT) mice engrafted human GBM, form the basis of our investigation. Results In situ hybridization for IDO1 revealed transcript expression throughout patient-resected GBM, whereas immunohistochemical IDO1 positivity was highly variable. Multivariate statistical analysis revealed that higher levels of IDO1 transcript predict a poor patient prognosis (P=0.0076). GBM IDO1 mRNA levels positively correlated with increased gene expression for markers of cytolytic and regulatory T cells, in addition to decreased patient survival. Humanized mice intracranially-engrafted human GBM revealed an IFNγ-associated T cell-mediated increase of intratumoral IDO1. Conclusions Our data demonstrate that high intratumoral IDO1 mRNA levels correlate with a poor GBM patient prognosis. It also confirms the positive correlation between increased GBM IDO1 levels and human-infiltrating T cells. Collectively, this study suggests that future efforts aimed at increasing T cell-mediated effects against GBM, should consider combinatorial approaches that co-inhibit potential T cell-mediated IDO1 enhancement during therapy.

Up‐regulation of indoleamine 2,3‐dioxygenase 1 (IDO1) expression and catalytic activity is associated with immunosuppression and poor prognosis in penile squamous cell carcinoma patients

“…In the present study, we found that IDO1 expression was positively correlated with the expression of the inhibitory checkpoint molecules PD-L1, PD-L2, PD-1, and CTLA-4, as well as the infiltration of suppressive immune cells, including Tregs, TAMs, and MDSCs, in agreement with previous reports in various solid tumors [29][30][31][32][33][34]. Unexpectedly, the upregulation of IDO1 expression was positively correlated with an increased density of CD8 + TILs in PSCC, which may be related to a poor prognosis.…”

IDO and intra‐tumoral neutrophils were independent prognostic factors for overall survival for hepatocellular carcinoma

“…Indole‐amine‐2,3‐dioxygenase (IDO) is responsible for the first enzymatic step of tryptophan catabolism by the kynurenine pathway performed as the rate‐limiting enzyme. Protein expression of IDO was found to be high in a number of tumor samples and contribute to decrease patient survival . IDO expression in various histologic cancer types seems to build an immune‐suppressive microenvironment by regulating immune cells such as T effector cells, Treg cells, and MDSC .…”

“…Protein expression of IDO was found to be high in a number of tumor samples and contribute to decrease patient survival. 3,4 IDO expression in various histologic cancer types seems to build an immune-suppressive microenvironment 5,6 by regulating immune cells such as T effector cells, 7 Treg cells, 8 and MDSC. 9,10 On the other hand, several studies have provided compelling evidence for pro-tumor functions of neutrophils by immune suppression.…”

Imaging tryptophan uptake with positron emission tomography in glioblastoma patients treated with indoximod

“…Namely, tryptophan dioxygenase (TDO), as well as tryptophan hydroxylase 1 (TPH1) and TPH2, collectively possess the ability to convert Trp into downstream metabolites. Although TDO is highly expressed in a majority of patient-resected GBM [9,50] it’s considered to be an unlikely contributor to AMT uptake, based on the high specificity for unmodified L -Trp [51,52]. In contrast, AMT is readily converted by TPH enzyme [53], and while the expression levels for the serotonergic pathway catalysts are currently unknown in GBM, they are the subject of an ongoing investigation.…”

“…The enzyme, indoleamine 2,3 dioxygenase (IDO1), is an attractive immunologic target for the treatment of GBM due to its high level of expression [9] and potently immunosuppressive activity [10]. IDO1 converts tryptophan (Trp) into kynurenine (Kyn), and depletion of Trp [11] or the accumulation of Kyn, have been demonstrated to suppress T cell effector functions and/or increase conversion of naïve CD4 + T cells into FoxP3 + regulatory T cells (Tregs) [12].…”