Differential Regulation of the Stimulator of Interferon Genes pathway in Human Papillomavirus positive and negative Head and Neck Cancers

Squamous cell carcinomas, which arise from the cells that line the mucosal surfaces of the head and neck, represent the most common type of head and neck cancers (HNSCCs). Human papillomavirus (HPV) Infection has been strongly associated with the development of oropharyngeal cancers, which are cancers that occur in the back of the throat, including the tonsils and base of the tongue. HNSCCs with and without HPV Infection have distinct pathology, with HPV positive patients having higher levels of immune infiltration, activation in the tumour microenvironment and better response to radiation and chemotherapy. It is however unclear whether HPV Infection in HNSCCs has the potential to activate innate immune sensing pathways and if these cancers possess intrinsic immunogenicity associated with HPV Infection. Here we investigate the innate immune stimulator of interferon genes (STING) pathway and immune responses to STING activation in HNSCCs and uncover fundamental differences in the regulation of this pathway in cell lines versus primary human clinical specimens. We show that while STING is differentially expressed in HPV positive and negative HNSCC cell lines, they exhibit a gross functional defect in signalling through this pathway. However, STING activation in immune cell populations generated immune signatures predicted to elicit useful tumoricidal mechanisms. In contrast, immunohistochemistry analysis of human tissue microarrays revealed enhanced STING expression in HPV related tumours and high intratumoral expression of STING correlated with increased survival.