Cancer‐associated fibroblast‐derived interleukin‐1β activates protumor C‐C motif chemokine ligand 22 signaling in head and neck cancer

• Published in: Cancer science Vol. 110; no. 9; pp. 2783 - 2793
• Main Authors: Huang, Yu‐Hsuan, Chang, Che‐Ying, Kuo, Yi‐Zih, Fang, Wei‐Yu, Kao, Hung‐Ying, Tsai, Sen‐Tien, Wu, Li‐Wha
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.09.2019; John Wiley and Sons Inc
• Subjects: Animals; Cancer therapies; Cancer-Associated Fibroblasts - immunology; Cancer-Associated Fibroblasts - metabolism; cancer‐associated fibroblast; CCL22; CCL22 protein; Cell Line, Tumor; Cell migration; Cell Movement - immunology; Cell proliferation; Cell Transformation, Neoplastic - immunology; Cell Transformation, Neoplastic - pathology; chemokine; Chemokine CCL22 - genetics; Chemokine CCL22 - metabolism; Chemokines; Cytokines; Disease-Free Survival; Female; Fibroblasts; Follow-Up Studies; Forkhead Transcription Factors - metabolism; Foxp3 protein; Gene expression; Gene Knockdown Techniques; Head & neck cancer; Humans; IL‐1β; Immune system; Immunoregulation; Interleukin-1beta - genetics; Interleukin-1beta - metabolism; Laboratory animals; Lymphatic system; Lymphocytes T; Male; Medical prognosis; Metastases; Metastasis; Mice; Middle Aged; Mouth Mucosa - pathology; Mouth Mucosa - surgery; Mouth Neoplasms - immunology; Mouth Neoplasms - mortality; Mouth Neoplasms - pathology; Mouth Neoplasms - surgery; Neoplasm Invasiveness - immunology; Neoplasm Invasiveness - pathology; Oral cancer; Original; Patients; Prognosis; Receptors, CCR4 - metabolism; Recruitment; RNA, Small Interfering - metabolism; Signal Transduction - immunology; Squamous Cell Carcinoma of Head and Neck - immunology; Squamous Cell Carcinoma of Head and Neck - mortality; Squamous Cell Carcinoma of Head and Neck - pathology; Squamous Cell Carcinoma of Head and Neck - surgery; Survival Analysis; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - metabolism; Tumorigenesis; Up-Regulation; Xenograft Model Antitumor Assays; Taiwan; cancer-associated fibroblast; chemokine; CCL22; IL-1β; oral cancer
• ISSN: 1347-9032; 1349-7006
• DOI: 10.1111/cas.14135

Oral cancer, a subtype of head and neck cancer, is characterized by increased infiltrating regulatory T cells (Treg); however, the pathological significance of the increase in Tregs in disease prognosis and progression and their underlying mechanism remain unestablished. C‐C motif chemokine ligand 22 (CCL22) has been implicated in the recruitment of Tregs. We used RT‐qPCR to determine CCL22 mRNA expression in clinical specimens and cultured cells. Loss‐of‐function and gain‐of‐function studies were carried out to analyze the effects of CCL22 modulations on cell proliferation, migration, invasion, and tumorigenesis and the mechanism involved in the deregulation of CCL22. In oral cancer specimens, CCL22 mRNA was upregulated. The increase was not only associated with reduced disease‐free survival but also strongly correlated with an increase in FOXP3 mRNA, a master regulator of Treg development and functions. Silencing CCL22 expression reduced cell proliferation, migration, and invasion, whereas ectopic overexpression showed opposite effects. Manipulation of CCL22 expression in cancer cells altered tumorigenesis in both immune‐compromised and ‐competent mice, supporting both autonomous and non‐autonomous actions of CCL22. Release of interleukin 1β (IL‐1β) from cancer‐associated fibroblasts (CAF) induces CCL22 mRNA expression in oral cancer cells by activating transcription factor nuclear factor kappa B (NF‐κB). Our data support a model in which CAF‐derived IL‐1β, CCL22, and its receptor CCR4 foster a protumor environment by promoting cell transformation and Treg infiltration. Intervention of the IL‐1β‐CCL22‐CCR4 signaling axis may offer a novel therapeutic strategy for oral cancer treatment. Increase of CCL22 expression was associated with reduced disease‐free survival and correlated with an increased expression of FOXP3, a master regulator of Treg development and function. CCL22 is an oncogene in oral cancer through both autonomous and non‐autonomous actions. Release of IL‐1β from cancer‐associated fibroblasts induces CCL22 mRNA expression in oral cancer cells through NF‐κB activation.