Constitutive Expression of the Immunosuppressive Tryptophan Dioxygenase TDO2 in Glioblastoma Is Driven by the Transcription Factor C/EBPβ.

Takumi Kudo,Soumya R Mohapatra,Wolfgang Wick,Felix Sahm,Ingrid Grummt,Mirja T Prentzell,Zhongliang Zhao,Christiane A Opitz,Edward W Green,Michael Platten

doi:10.3389/fimmu.2020.00657

Abstract

Catabolism of the essential amino acid tryptophan is a key metabolic pathway contributing to the immunosuppressive tumor microenvironment and therefore a viable drug target for cancer immunotherapy. In addition to the rate-limiting enzyme indoleamine-2,3-dioxygenase-1 (IDO1), tryptophan catabolism via tryptophan-2,3-dioxygenase (TDO2) is a feature of many tumors, particularly malignant gliomas. The pathways regulating TDO2 in tumors are poorly understood; using unbiased promoter and gene expression analyses, we identify a distinct CCAAT/enhancer-binding protein β (C/EBPβ) binding site in the promoter of TDO2 essential for driving constitutive TDO2 expression in glioblastoma cells. Using The Cancer Genome Atlas (TCGA) data, we find that C/EBPβ expression is correlated with TDO2, and both are enriched in malignant glioma of the mesenchymal subtype and associated with poor patient outcome. We determine that TDO2 expression is sustained mainly by the LAP isoform of CEBPB and interleukin-1β, which activates TDO2 via C/EBPβ in a mitogen-activated protein kinase (MAPK) kinase-dependent fashion. In summary, we provide evidence for a novel regulatory and therapeutically targetable pathway of immunosuppressive tryptophan degradation in a subtype of glioblastoma with a particularly poor prognosis.

Highlights

Malignant gliomas are characterized by profound local and systemic immunosuppression [1], which blunts the efficacy of the novel immunotherapeutic treatments for malignant gliomas [2]
We have recently demonstrated that prostaglandins, prostaglandin E2 (PGE2), enhance TDO2 expression and enzymatic activity in malignant gliomas via activation of the prostaglandin E receptor-4 (EP4) [38]
In contrast to previous approaches, here, we used an unbiased search for regulators of constitutive TDO2 expression in a GBM cell line using iteratively deleted TDO2 reporter constructs to show that CCAAT/enhancer-binding protein β (C/EBPβ) plays an important role in driving TDO2 expression in glioma cells

Summary

Introduction

Malignant gliomas are characterized by profound local and systemic immunosuppression [1], which blunts the efficacy of the novel immunotherapeutic treatments for malignant gliomas [2]. Trp metabolism promotes local immune tolerance by both inducing anergy and apoptosis of CD8-positive T cells, and activating regulatory T (Treg) cells, mainly through accumulation of immunosuppressive Kyn [12, 13]. TDO2 has been shown to be expressed in many tumors and to promote tumor growth by suppressing antitumor immune responses in a similar fashion [17,18,19,20] (Supplementary Figure S1). In contrast to IDO1, whose regulation has been thoroughly characterized and involves tumor suppressor genes [21], oncogenes [22], growth factor/cytokine signaling pathways [23], and epigenetic mechanisms [24], the regulation of TDO2 in gliomas is not well understood. We employed an unbiased approach to identify transcriptional regulators of TDO2

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Conclusion