Journal Article

Dysbiotic oral microbiota-derived kynurenine, induced by chronic restraint stress, promotes head and neck squamous cell carcinoma by enhancing CD8+ T cell exhaustion

Pu, Juncai, Luo, Shihong, Xie, Peng, Yan, Li, Yang, Bing, Kang, Ning, Ji, Ping, Jin, Xin, Wang, Haiyang, Cannon, Richard D, Lou, Fangzhi, Dong, Yunmei, Xu, Jingyi, Liu, Yiyun

2025

Overview

BackgroundChronic restraint stress (CRS) is a tumour-promoting factor. However, the underlying mechanism is unknown.ObjectiveWe aimed to investigate whether CRS promotes head and neck squamous cell carcinoma (HNSCC) by altering the oral microbiota and related metabolites and whether kynurenine (Kyn) promotes HNSCC by modulating CD8+ T cells.Design4-nitroquinoline-1-oxide (4NQO)-treated mice were exposed to CRS. Germ-free mice treated with 4NQO received oral microbiota transplants from either CRS or control mouse donors. 16S rRNA gene sequencing and liquid chromatography-mass spectrometry were performed on mouse saliva, faecal and plasma samples to investigate alterations in their microbiota and metabolites. The effects of Kyn on HNSCC were studied using the 4NQO-induced HNSCC mouse model.ResultsMice subjected to CRS demonstrated a higher incidence of HNSCC and oral microbial dysbiosis than CRS-free control mice. Pseudomonas and Veillonella species were enriched while certain oral bacteria, including Corynebacterium and Staphylococcus species, were depleted with CRS exposure. Furthermore, CRS-altered oral microbiota promoted HNSCC formation, caused oral and gut barrier dysfunction, and induced a host metabolome shift with increased plasma Kyn in germ-free mice exposed to 4NQO treatment. Under stress conditions, we also found that Kyn activated aryl hydrocarbon receptor (AhR) nuclear translocation and deubiquitination in tumour-reactive CD8+ T cells, thereby promoting HNSCC tumourigenesis.ConclusionCRS-induced oral microbiota dysbiosis plays a protumourigenic role in HNSCC and can influence host metabolism. Mechanistically, under stress conditions, Kyn promotes CD8+ T cell exhaustion and HNSCC tumourigenesis through stabilising AhR by its deubiquitination.

• Publisher: BMJ Publishing Group Ltd and British Society of Gastroenterology,BMJ Publishing Group LTD,BMJ Publishing Group
• Subject: 4-Nitroquinoline-1-oxide / Animal models / Animals / Antigens / CANCER / Carbohydrates / CARCINOGEN METABOLISM / CD8 antigen / CD8-Positive T-Lymphocytes - immunology / CD8-Positive T-Lymphocytes - metabolism / Chromatography / Disease Models, Animal / Dysbacteriosis / Dysbiosis - complications / Dysbiosis - metabolism / Dysbiosis - microbiology / EPITHELIAL BARRIER / Feces / Germfree / Gut Microbiota / Head & neck cancer / Head and neck carcinoma / Head and Neck Neoplasms - etiology / Head and Neck Neoplasms - immunology / Head and Neck Neoplasms - metabolism / Head and Neck Neoplasms - microbiology / Hormones / IMMUNOREGULATION / Kynurenine - metabolism / Liquid chromatography / Lymphocytes T / Male / Mass spectroscopy / Medical diagnosis / Metabolism / Metabolites / Mice / Mice, Inbred C57BL / Microbiota / Microorganisms / Mouth - microbiology / Neck / Nuclear transport / Oral carcinoma / Original Research / Restraint, Physical / rRNA 16S / Saliva / Software / Squamous cell carcinoma / Squamous Cell Carcinoma of Head and Neck - etiology / Squamous Cell Carcinoma of Head and Neck - immunology / Squamous Cell Carcinoma of Head and Neck - metabolism / Squamous Cell Carcinoma of Head and Neck - microbiology / Statistical analysis / Stress / Stress, Psychological - complications / Stress, Psychological - metabolism / Stress, Psychological - microbiology / T-Cell Exhaustion / Tongue / Tumorigenesis / Tumors