Targeting the aryl hydrocarbon receptor (AhR) with BAY 2416964: a selective small molecule inhibitor for cancer immunotherapy

• DOI: 10.1136/jitc-2023-007495
• Publication Date: 2023-11-14T17:10:33Z
• Authors: Christina Kober; Julian Roewe; Norbert Schmees; Lars Roese; Ulrike Roehn; Benjamin Bader; Detlef Stoeckigt; Florian Prinz; Mátyás Gorjánácz; Helge Gottfried R...; Catherine Olesch; Gabriele Leder; Horst Irlbacher; Ralf Lesche; Julien Lefranc; Mine Oezcan-Wahlb...; Ankita Sati Batra; Nirmeen Elmadany; Rafael Carretero; Katharina Sahm; Iris Oezen; Frederik Cichon; Daniel Baumann; Ahmed Sadik; Christiane A Opitz; Hilmar Weinmann; Ingo V Hartung; Bertolt Kreft; Rienk Offringa; Michael Platten; Ilona Gutcher
• Keywords: Cancer Immunotherapy

Background The metabolism of tryptophan to kynurenines (KYN) by indoleamine-2,3-dioxygenase or tryptophan-2,3-dioxygenase is a key pathway constitutive and adaptive tumor immune resistance. immunosuppressive effects KYN in the microenvironment are predominantly mediated aryl hydrocarbon receptor (AhR), cytosolic transcription factor that broadly suppresses cell function. Inhibition AhR thus offers an antitumor therapy opportunity via restoration system functions. Methods expression was evaluated tissue microarrays head neck squamous carcinoma (HNSCC), non-small lung cancer (NSCLC) colorectal (CRC). A structure class inhibitors block activation exogenous endogenous ligands identified, further optimized, using cellular screening cascade. antagonistic properties selected inhibitor candidate BAY 2416964 were determined transactivation assays. Nuclear translocation, target engagement effect on agonist-induced assessed human mouse cells. immunostimulatory gene cytokine examined subsets. vivo efficacy tested syngeneic ovalbumin-expressing B16F10 melanoma model mice. Coculture H1299 NSCLC cells, primary peripheral blood mononuclear cells fibroblasts mimicking stromal-tumor used assess inhibition Furthermore, spheroids cocultured with antigen-specific MART-1 T study cytotoxic responses. data analyzed statistically linear models. Results observed tumor-infiltrating HNSCC, CRC. potently selectively inhibited induced either ligands. In vitro, restored function furthermore enhanced responses killing spheroids. vivo, oral application well tolerated, proinflammatory microenvironment, demonstrated Conclusions These findings identify as novel therapeutic approach overcome resistance various types cancers.