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Title (Primary) Constitutive IDO expression in human cancer is sustained by an autocrine signaling loop involving IL-6, STAT3 and the AHR
Author Litzenburger, U.M.; Opitz, C.A.; Sahm, F.; Rauschenbach, K.J.; Trump, S.; Winter, M.; Ott, M.; Ochs, K.; Lutz, C.; Liu, X.; Anastasov, N.; Lehmann, I.; Höfer, T.; von Deimling, A.; Wick, W.; Platten, M.;
Journal Oncotarget
Year 2014
Department IMMU;
Volume 5
Issue 4
Language englisch;
POF III (all) T42; F11;
UFZ wide themes RU3;
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.
ID 14754
Persistent UFZ Identifier https://www.ufz.de/index.php?en=20939&ufzPublicationIdentifier=14754
Litzenburger, U.M., Opitz, C.A., Sahm, F., Rauschenbach, K.J., Trump, S., Winter, M., Ott, M., Ochs, K., Lutz, C., Liu, X., Anastasov, N., Lehmann, I., Höfer, T., von Deimling, A., Wick, W., Platten, M. (2014):
Constitutive IDO expression in human cancer is sustained by an autocrine signaling loop involving IL-6, STAT3 and the AHR
Oncotarget 5 (4), 1038 - 1051