BBB seminar: Christiane Opitz
Metabolic signalling through the aryl hydrocarbon receptor as a regulator of anti-tumor immunity
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NB! The below seminar has been replaced by the following:听BBB seminar by Christine Sers. Same time and place.
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Brain Cancer Metabolism Group, German Consortium of Translational Cancer Research (DKTK) & German Cancer Research Center (DKFZ), Heidelberg, Germany
The aryl hydrocarbon receptor (AHR) is a master regulator of cancer by modulating both tumor cell intrinsic malignant properties as well as anti-tumor immunity. Indoleamine-2,3-dioxygenase-1 (IDO1) and tryptophan-2,3-dioxygenase (TDO2) are hitherto recognized as the main AHR-activating enzymes. Due to its context-specific regulation, reliable detection of AHR activity across human tissues is difficult. To overcome this issue, we developed a ligand and tissue independent AHR signature by combined natural language processing and gene expression analysis. Systematically investigating AHR activity in human cancers, we found across 32 tumor entities that interleukin-4-induced-1 (IL4I1) associates more frequently with AHR activity than IDO1 or TDO2. IL4I1 is the key enzyme of a novel Trp-metabolic pathway in humans that activates the AHR, and promotes cancer cell motility and immune suppression. Immune checkpoint blockade (ICB) induces IL4I1 alongside IDO1, suggesting a contribution of IL4I1 to ICB resistance. Clinical studies combining ICB with IDO1 inhibitors have failed. Being a more potent AHR activator than IDO1 and TDO2, IL4I1 may compensate for IDO1 and TDO2 blockade. As we find that IDO1 inhibitors do not block IL4I1, this may explain the failure of IDO1 inhibition. Our results thus suggest that pan-Trp catabolism inhibitors or AHR inhibitors will open new avenues for cancer therapy.
Chairperson:听Mathias Ziegler, Department of Biomedicine
