Comparison of Interleukin-1 Ligand Expression by Human Papilloma Virus Status in HNSCCs

Interleukin-1 alpha (IL-1α) is a cytokine involved in the acute phase immune response and its expression is upregulated in a variety of solid tumors including head and neck squamous cell carcinomas (HNSCCs). Tumor expression of IL-1α is associated with increased tumor aggressiveness in HNSCCs, but this has yet to be studied in the context of human papilloma virus (HPV) status. This study is aimed at determining differences in tumor expression and subcellular localization of IL-1α in HPV-positive (HPV+) and HPV-negative (HPV-) HNSCC tumors. Tissue microarrays (TMAs) containing HPV+ (n = 31) and HPV- (n = 47) primary and metastatic HNSCCs were analyzed for IL-1α expression using immunohistochemical (IHC) staining. HPV status was confirmed using p16 IHC staining and RNA in situ hybridization (RNA ISH). Differences in IL-1α protein expression and secretion in HPV+ and HPV- HNSCC cell lines were determined by western blot and ELISA respectively. Associations between tumor IL1A expression and survival outcomes were assessed in HPV+ and HPV- HNSCC patients from publicly available gene expression datasets. Tumor expression of IL-1α was significantly increased in HPV- tumors and cell lines (as detected by IHC and western blot respectively) compared to HPV+ tumors and cell lines. There was no difference in IL-1α release between HPV+ and HPV- cell lines. IL-1α was expressed in both nuclear and cytoplasmic compartments, with predominant expression in the nucleus. Gene expression of IL1A was significantly increased in HPV-tumors/cell lines compared to HPV+ tumors/cell lines. Lastly, increased IL1A gene expression was significantly associated with worse survival in HPV- tumors but not in HPV+ tumors. Overall IL-1α expression particularly in the nucleus may possess more prognostic significance in HPV- tumors rather than HPV+ tumors. This work warrants further investigation into the role of intracellular IL-1α ligand expression in HNSCCs and may have important implications in IL-1 pathway blockade as therapeutic strategy.