Impact of aryl hydrocarbon receptor (AHR) modulation on survival in pre-clinical head and neck models via microbial tryptophan pathway.

e14594 Background: Metastatic head and neck squamous cell carcinoma (HNSCC) remains associated with poor outcomes. We have previously demonstrated that microbial tryptophan metabolites are associated with resistance to immune checkpoint blockade, likely through modulation of aryl hydrocarbon receptor (AhR) signaling. Based on this rationale, we evaluated the efficacy of a novel AhR-modulating combination regimen to improve progression-free and overall survival. Methods: Using a syngeneic HNSCC mouse model implanted with MOC1 cells, ten mice were treated with a novel AhR-modulating combination (JS0001). Tumor volume was measured twice weekly until humane endpoint. Mice treated with standard-of-care anti-mouse programmed cell death-1 (anti-PD-1) antibody served as controls. Results: Treatment with JS0001 resulted in a significant reduction in tumor growth rate and improved progression-free survival compared with controls (tumor growth slope estimate −0.87, SE 0.02; p < 0.00001). To investigate mechanisms underlying differential tumor response, systemic and tumor metabolomic profiling was performed. Treatment was associated with significant systemic reductions in multiple microbial tryptophan metabolites, with the strongest effect observed for indole-3-pyruvic acid (IPyA; percent change per day −1.3%, adjusted p < 0.002). Concordant intratumoral reductions in IPyA and indole acetaldehyde (IAAld) were observed in treated mice (estimates 0.70 and 0.47, respectively; p < 0.05). Conclusions: These data support AhR modulation as a strategy to enhance antitumor efficacy and provide preclinical justification for evaluating this novel combination in early-phase clinical trials.