Isocitrate dehydrogenase mutations suppress STAT1 and CD8+ T cell accumulation in gliomas

Kohanbash, Gary; Carrera, Diego; Shrivastav, Shruti; Ahn, Brian; Jahan, Naznin; Mazor, Tali; Chheda, Zinal; Downey, Kira; Watchmaker, Payal; Beppler, Casey; Warta, Rolf; Amankulor, Nduka; Herold‐Mende, Christel; Costello, J; Okada, Hideho

doi:10.1172/jci90644

Cited by 347 publications

(328 citation statements)

References 64 publications

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“…3A, B, showing the inverse association between the presence of mIDH and decreased intratumoral IDO1 levels. Given that mIDH suppresses CD8 + Tc cell accumulation in glioma (37), in addition to the favorable prognosis it carries for GBM patient survival (38), it is tempting to speculate that the mIDH suppression of GBM-infiltrating Tc increases patient survival by virtue of the additional suppression of IDO1 and Treg accumulation in those patient tumors.…”

Section: Discussionmentioning

confidence: 99%

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

Zhai

Ladomersky

Lauing

et al. 2017

Clinical Cancer Research

143

137

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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.

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Section: Discussionmentioning

confidence: 99%

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

Zhai

Ladomersky

Lauing

et al. 2017

Clinical Cancer Research

143

137

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“…Treatment of T cells with the “oncometabolite” 2-hydroxyglutarate (2-HG), generated at high levels by tumors expressing mutant forms of IDH (Dang et al, 2009), results in reduced effector character (Tyrakis et al, 2016). Mutant IDH tumors generate an immunosuppressive environment through high concentrations of 2-HG at the tumor site that can be overcome by the pharmacological inhibition of 2-HG production by tumor cells (Kohanbash et al, 2017). Taken together, these results suggest that the inhibition of T cell metabolism by the metabolic activity of tumor cells is an important mechanism of immunosuppression in the tumor.…”

Section: T Cells Face a Hostile Tumor Environment With Fierce Competimentioning

confidence: 99%

Metabolic Regulation of T Cell Longevity and Function in Tumor Immunotherapy

2017

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Summary Cancer immunotherapy is an increasingly successful strategy for the treatment of patients who have advanced or conventional therapy-resistant cancers. T cells are key mediators of tumor destruction and their specificity for tumor-expressed antigens is of paramount importance, but other T cell-intrinsic qualities such as durability, longevity and functionality also play important roles in determining the efficacy of immunotherapy. The cellular energetic pathways that are utilized by T cells play a key role in regulating each of these qualities. Metabolic activity, which both regulates and is regulated by cellular signaling pathways and epigenetics, also profoundly influences the trajectories of T cell differentiation and fate. In this review, we discuss how cell metabolism influences T cell anti-tumor activity, the metabolic qualities of highly-functional T cells and strategies to modulate metabolism for improving the immune response to tumors.

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“…6,7,[9][10][11][12][13] IDHmut and IDHwt tumors differ with regards to various biological processes, including immune cell infiltration. [14][15][16][17] Human IDH1-mutant gliomas have less infiltrating immune cells than IDH1-wild type gliomas, with global depletion of immune infiltrates, including microglia, macrophages, dendritic cells, B cells, and T cells. Accordingly, early IDHmut glioma progenitor cells have suppressed immunity compared with IDHwt cells, 4,15,18 which may be responsible for their improved clinical outcomes.…”

Section: Introductionmentioning

confidence: 99%

ISG20 promotes local tumor immunity and contributes to poor survival in human glioma

et al. 2018

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Recent evidence has confirmed that a mutation of the isocitrate dehydrogenase (IDH) gene occurs early in gliomagenesis and contributes to suppressed immunity. The present study aimed to determine the candidate genes associated with IDH mutation status that could serve as biomarkers of immune suppression for improved prognosis prediction. Clinical information and RNA-seq gene expression data were collected for 932 glioma samples from the CGGA and TCGA databases, and differentially expressed genes in both lower-grade glioma (LGG) and glioblastoma (GBM) samples were identified according to IDH mutation status. Only one gene, interferon-stimulated exonuclease gene 20 (ISG20), with reduced expression in IDH mutant tumors, demonstrated significant prognostic value. ISG20 expression level significantly increased with increasing tumor grade, and its high expression was associated with a poor clinical outcome. Moreover, increased ISG20 expression was associated with increased infiltration of monocyte-derived macrophages and neutrophils, and suppressed adaptive immune response. ISG20 expression was also positively correlated with PD-1, PD-L1, and CTLA4 expression, along with the levels of several chemokines. We conclude that ISG20 is a useful biomarker to identify IDH-mediated immune processes in glioma and may serve as a potential therapeutic target.

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Isocitrate dehydrogenase mutations suppress STAT1 and CD8+ T cell accumulation in gliomas

Cited by 347 publications

References 64 publications

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

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

Metabolic Regulation of T Cell Longevity and Function in Tumor Immunotherapy

ISG20 promotes local tumor immunity and contributes to poor survival in human glioma

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