No abstract

Head and neck squamous cell carcinoma (HNSCC) is a highly aggressive solid tumor, with a 5-year mortality rate of ~50%. The development of immunotherapies has improved the survival of patients with HNSCC, but, the long-term prognosis of patients with recurrent or metastatic HNSCC remains poor. HNSCC is characterized by intratumoral infiltration of regulatory T cells, dysfunctional natural killer cells, an elevated Treg/CD8+ T cell ratio, and increased programmed cell death ligand 1 protein on tumor cells. This leads to an immunocompromised niche in favor of the proliferation and treatment resistance of cancer cells. To achieve an improved treatment response, several potential combination strategies, such as increasing the neoantigens for antigen presentation and therapeutic agents targeting components of the tumor microenvironment, have been explored and have shown promising results in preclinical studies. In addition, large-scale bioinformatic studies have also identified possible predictive biomarkers of HNSCC. As immunotherapy has shown survival benefits in recent HNSCC clinical trials, a comprehensive investigation of immune cells and immune-related factors/cytokines and the immune profiling of tumor cells during the development of HNSCC may provide more insights into the complex immune microenvironment and thus, facilitate the development of novel immunotherapeutic agents.

NOD1 (nucleotide-binding oligomerization domain 1) is overexpressed in head and neck squamous cell carcinoma (HNSCC) cells, as is IL-8 in cancer cells. However, the mechanism of the IL-8-mediated overexpression of NOD in HNSCC not been identified. This study determines whether IL-8 promotes tumor progression via the NOD signaling pathway in HNSCC. Higher IL-8, NOD1 and receptor-interacting protein kinase (RIP2) expressions were observed in HNSCC tissue than in non-cancerous matched tissue (NCMT), whereas NOD2 was weakly expressed. Furthermore, IL-8 stimulated the proliferation of HNSCC cells (SCC4, SCC9 and SCC25) but not dysplastic oral mucosa DOK cells. Exposure to IL-8 increased the clonogenicity of HNSCC cells. IL-8 siRNA inhibited cell proliferation and cell colony formation, suggesting that IL-8 is involved in HNSCC cancer progression. The expressions of CXCR1 and CXCR2 were higher in HNSCC tissue than in NCMT. HNSCC cells that were exposed to IL-8 exhibited higher expression of CXCR1/2 than did controls. The blocking of IL-8 by siRNA reduced CXCR1/2 expression in HNSCC cells, suggesting that the cancer progression of HNSCC cells that is induced by IL-8 depends on CXCR1/2. Additionally, IL-8 is associated with increased NOD1 and RIP2 expression and reduced NOD2 expression in three types of HNSCC cells. The blocking of IL-8 by siRNA reduces IL-8, NOD1 and RIP2 expressions in HNSCC cells, but not the level of NOD2. These results suggest that IL-8 has an important role in HNSCC progression via a CXCR1/2-meidated NOD1/RIP2 signaling pathway.