Abstract 1210: Targeting the IDO1-Kynurenine-AhR pathway for cancer immunotherapy

The aryl hydrocarbon receptor (AhR) is a ligand-controlled transcription factor that is primarily known to be a sensor of xenobiotics and tumor-promoting activities of halogenated hydrocarbons and polycyclic aromatic hydrocarbons. Several endogenous ligands such as metabolites produced by commensal microorganisms on skin and in gut and metabolites of L-Tryptophan - produced under control of the Tryptophan dioxygenases IDO1 and TDO2 such as L-Kynurenine and Kynurenic acid are known to modulate the transcriptional activity of AhR. The activity of AhR is predominant in many different immune and epithelial cells, thereby balancing immune responses towards various signals. Activation of the IDO1-Kyn-AhR pathway and accumulation of nuclear AhR protein is frequently seen in different tumor types and possibly linked to the observed diminished anti-tumor immune response. AhR agonizing ligands produced by cancer cells and/or lymphocytes recruited to the TME reduce the anti-tumor immune response through increasing the numbers and function of regulatory T cells while reducing that of cytotoxic CD8+ T cells. In order to reduce AhR-mediated immune-suppression in cancer patients, Phenex Pharmaceuticals initiated a program to identify small molecule AhR antagonists to block activated downstream signaling of AhR. To this end, we have identified novel AhR antagonists, which showed strong antagonistic activity against agonist-activated human AhR in a cell based CYP1A1 promoter-driven luciferase reporter assay in HepG2 cells. The compound series display good oral bioavailability and low clearance in mice. Our AhR antagonist molecules show single agent anti-tumor activity and increase the efficacy of Gemcitabine and anti-PD-L1 checkpoint inhibition in different syngeneic mouse tumor models. Overall, AhR antagonist treatment increased CD8+ T cell and M1 macrophage numbers, and decreased IL22 levels, which might be of functional relevance in the tumor context. Future research is directed to determine PK-PD markers suitable for clinical development and identification of human malignancies likely of responding to AhR antagonist treatment. Citation Format: Sheena Pinto, Christoph Steeneck, Michael Albers, Simon Anderhub, Manfred Birkel, Larisa Buselic-Wolfel, Gisela Eisenhardt, Claus Kremoser, Thomas Hoffmann, Ulrich Deuschle. Targeting the IDO1-Kynurenine-AhR pathway for cancer immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1210.