Experimental hematology & oncology
Blocking aryl hydrocarbon receptor remodels myeloid-T cell crosstalk and enhances anti-PD-1 response in the tumor microenvironment
By Kim DK, Baek S, Kim Y and 11 others.
Abstract
Purpose
Cancer metabolism-associated immune suppression remains a major barrier to durable therapeutic responses. Indoleamine-2,3-dioxygenase 1 has been pursued as a therapeutic target, but incomplete pathway suppression has limited clinical success. As the aryl hydrocarbon receptor is a ligand-activated transcription factor and downstream effector of tryptophan metabolism, we investigated how myeloid-cell aryl hydrocarbon receptor signaling shapes the tumor immune microenvironment and whether its inhibition can restore antitumor immunity.
Methods
Conditional aryl hydrocarbon receptor knockout mice targeting dendritic cells or macrophages were used to evaluate the effects of genetic aryl hydrocarbon receptor ablation. Pharmacologic inhibition was assessed using DA-4505 across syngeneic lung, colorectal, and breast cancer models and an immune checkpoint inhibitor-refractory humanized patient-derived xenograft model. Therapeutic efficacy was evaluated alone or in combination with anti-programmed cell death protein 1 therapy, chemotherapy, or surgery. Tumor growth, survival, metastasis, and immune remodeling were analyzed by flow cytometry, multiplex immunohistochemistry, single-cell RNA sequencing, cytokine profiling, and human tumor datasets.