title: Tryptophan-2,3-dioxygenase is regulated by prostaglandin E2 in malignant glioma via a positive signaling loop involving prostaglandin E receptor-4.
abstract: Malignant gliomas and other types of tumors generate a local immunosuppressive microenvironment, which prohibits an effective anti-tumor immune response and promotes tumor growth. Along with others, we have recently demonstrated that catabolism of the essential amino acid tryptophan via tryptophan-2,3-dioxygenase (TDO) is an important mechanism mediating tumor-associated immunosuppression particularly in gliomas. The pathways regulating TDO in tumors, however, are poorly understood. Here, we show that prostaglandins enhance TDO expression and enzymatic activity in malignant gliomas via activation of prostaglandin E receptor-4 (EP4). Stimulation with prostaglandin E2(PGE2) up-regulated TDO-mediated kynurenine release in human glioma cell lines, whereas knockdown of the PGE2receptor EP4 inhibited TDO expression and activity. In human malignant glioma tissue expression of the PGE2-producing enzyme cyclooxygenase-2 (COX2) and its receptor EP4 were associated with TDO expression both on transcript and protein level. High expression of EP4 correlated with poor survival in malignant glioma patients WHO III-IV. Importantly, treatment of glioma cells with an EP4 inhibitor decreased TDO expression and activity. Moreover, TDO-over-expressing murine gliomas showed increased COX2 and EP4 expression suggesting a positive feedback mechanism in vivo. In summary, targeting EP4 may inhibit - in addition to immunosuppressive COX2 signaling - tryptophan degradation as another important immunosuppressive pathway and thus, could provide a dual clinically relevant immunotherapeutic avenue for the treatment of malignant gliomas. We proposed that in malignant gliomas prostaglandin E2(PGE2) produced by cyclooxygenases (COX) up-regulates tryptophan-2,3-dioxygenase (TDO) expression and enzyme activity through binding to its Gs-coupled receptor EP4 and therefore may mediate tumor immune escape in part through aryl hydrocarbon receptor (AHR) activation. Moreover, TDO activity itself seems to induce intratumoral PGE2metabolism suggesting an immunosuppressive loop involving COX/EP4/TDO.
authors.affiliation: Department of Neurology, University Hospital Heidelberg and National Center for Tumor Diseases, Heidelberg, Germany.|Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Ochs
authors.affiliation: Department of Neurology, University Hospital Heidelberg and National Center for Tumor Diseases, Heidelberg, Germany.|Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Ott
authors.affiliation: Department of Neurology, University Hospital Heidelberg and National Center for Tumor Diseases, Heidelberg, Germany.|Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Katharina J
authors.initials: KJ
authors.lastname: Rauschenbach
authors.affiliation: Department of Neurology, University Hospital Heidelberg and National Center for Tumor Diseases, Heidelberg, Germany.|Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Deumelandt
authors.affiliation: Department of Neuropathology, University Hospital Heidelberg, Heidelberg, Germany.|Clinical Cooperation Unit Neuropathology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Felix
authors.initials: F
authors.lastname: Sahm
authors.affiliation: Department of Neurology, University Hospital Heidelberg and National Center for Tumor Diseases, Heidelberg, Germany.|Brain Cancer Metabolism Group, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Christiane A
authors.initials: CA
authors.lastname: Opitz
authors.affiliation: Department of Neuropathology, University Hospital Heidelberg, Heidelberg, Germany.|Clinical Cooperation Unit Neuropathology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: von Deimling
authors.affiliation: Department of Neurology, University Hospital Heidelberg and National Center for Tumor Diseases, Heidelberg, Germany.|Clinical Cooperation Unit Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Wick
authors.affiliation: Department of Neurology, University Hospital Heidelberg and National Center for Tumor Diseases, Heidelberg, Germany.|Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Platten
keywords: glioma; immunosuppression; prostaglandin; tryptophan-2,3-dioxygenase