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Alterations in host immunity, inflammation, angiogenesis, and metabolism have been noted to be prominent clinical features in patients with head and neck squamous cell carcinoma (HNSCC). IL-1β, a prototypical inflammatory cytokine, is induced and activated following infection and tissue damage. High IL-1 levels in the tumor microenvironment are associated with a more aggressive tumor phenotype and generally poor prognoses. It was reported that single-nucleotide polymorphisms (SNPs) identified in IL1B gene influence the risk of many kinds of cancer, but the role of IL1B in the development and progress of HNSCC and the related molecular mechanism were not well understood. In the present study, we found IL1B was upregulated in tongue cancer tissues according to our RNA-Seq data and was validated in other 60 paired clinical samples. Using data from The Cancer Genome Atlas (TCGA) head and neck squamous cell carcinoma (HNSC), we found that the expression of IL1B in HNSCC tumor samples (n=501) is significantly higher than the adjacent noncancer tissues (n=44) and hypomethylation of CpG sites was found around the promoter region of IL1B in the cancer samples. Regression analysis identified a moderately negative correlation between IL1B expression and the DNA methylation of these CpG sites, even though there is not CpG island around its promoter. Knockdown of IL1B in Cal-27 and TCA-8113 tongue cancer cells inhibited cell proliferation, migration and invasion ability, and overexpression of IL1B or recombinant IL1B protein can promote proliferation, migration and invasion of tongue cancer cells. The results indicated that aberrant IL1B expression might be modulated by its DNA hypomethylation and IL1B produced by cancer cells can promote tumor progression and metastasis, and the inhibition of IL1B pathway may be a novel therapeutic approach in the treatment of HNSCC. Citation Format: Dali Zheng, Weitao Chen, Youguang Lu. Epigenetic activated IL1B promotes tumor progression of tongue cancer [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr A54.