title: Constitutive IDO expression in human cancer is sustained by an autocrine signaling loop involving IL-6, STAT3 and the AHR.
abstract: Indoleamine-2,3-dioxygenase (IDO) inhibitors have entered clinical trials based on their ability to restore anti-tumor immunity in preclinical studies. However, the mechanisms leading to constitutive expression of IDO in human tumors are largely unknown. Here we analyzed the pathways mediating constitutive IDO expression in human cancer. IDO-positive tumor cells and tissues showed basal phosphorylation and acetylation of STAT3 as evidenced by western blotting and immunoprecipitation. Inhibition of IL-6 or STAT3 using siRNA and/or pharmacological inhibitors reduced IDO mRNA and protein expression as well as kynurenine formation. In turn, IDO enzymatic activity activated the AHR as shown by the induction of AHR target genes. IDO-mediated AHR activation induced IL-6 expression, while inhibition or knockdown of the AHR reduced IL-6 expression. IDO activity thus sustains its own expression via an autocrine AHR-IL-6-STAT3 signaling loop. Inhibition of the AHR-IL-6-STAT3 signaling loop restored T-cell proliferation in mixed leukocyte reactions performed in the presence of IDO-expressing human cancer cells. Identification of the IDO-AHR-IL-6-STAT3 signaling loop maintaining IDO expression in human cancers reveals novel therapeutic targets for the inhibition of this core pathway promoting immunosuppression of human cancers. The relevance of the IDO-AHR-IL-6-STAT3 transcriptional circuit is underscored by the finding that high expression of its members IDO, STAT3 and the AHR target gene CYP1B1 is associated with reduced relapse-free survival in lung cancer patients.
authors.affiliation: Department of Neurooncology, Neurology Clinic and National Center for Tumor Diseases University Hospital of Heidelberg, Heidelberg, Germany.
authors.forename: Ulrike M
authors.initials: UM
authors.lastname: Litzenburger
authors.forename: Christiane A
authors.initials: CA
authors.lastname: Opitz
authors.forename: Felix
authors.initials: F
authors.lastname: Sahm
authors.forename: Katharina J
authors.initials: KJ
authors.lastname: Rauschenbach
authors.forename: Saskia
authors.initials: S
authors.lastname: Trump
authors.forename: Marcus
authors.initials: M
authors.lastname: Winter
authors.forename: Martina
authors.initials: M
authors.lastname: Ott
authors.forename: Katharina
authors.initials: K
authors.lastname: Ochs
authors.forename: Christian
authors.initials: C
authors.lastname: Lutz
authors.forename: Xiangdong
authors.initials: X
authors.lastname: Liu
authors.forename: Natasa
authors.initials: N
authors.lastname: Anastasov
authors.forename: Irina
authors.initials: I
authors.lastname: Lehmann
authors.forename: Thomas
authors.initials: T
authors.lastname: Höfer
authors.forename: Andreas
authors.initials: A
authors.lastname: von Deimling
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Wick
authors.forename: Michael
authors.initials: M
authors.lastname: Platten
mesh_terms: D000107:Acetylation; D017209:Apoptosis / Q000502:physiology; D019898:Autocrine Communication; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000502:physiology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000096:biosynthesis* / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism*; D008175:Lung Neoplasms / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D009369:Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D010051:Ovarian Neoplasms / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D015850:Interleukin-6; D018336:Receptors, Aryl Hydrocarbon; D050796:STAT3 Transcription Factor; C111235:AHR protein, human; C508600:IL6 protein, human; C494086:STAT3 protein, human