The incidence of Human Papillomavirus positive (HPV+) head and neck squamous cell carcinoma (HNSCC) threatens the health of thousands of people each year, with cases projected to rise in the coming decade. HPV is now the etiologic agent accountable for nearly all oropharyngeal cancers. Despite the effectiveness and relatively favorable prognosis of current treatments for HPV+ HNSCC, many patients do not respond and are left facing uncertainty about their health and future. What is sure is that there is an urgent need to develop novel strategies for the treatment of HPV+ HNSCC. Viruses have evolved a myriad of mechanisms to evade the immune system. Some high-risk HPV strains can elude detection by disrupting host DNA methylation patterns, altering genome-wide cellular transcription, and depleting key signaling molecules necessary for the infected cell to mount an effective immune response. Including those that are initiated by viruses, the epigenetic dysregulation of DNA methylation or chromatin structure has been observed in tumor cells across many cancers. This suggests that there are common mechanisms that both viruses and tumor cells can exploit to evade immune detection, predisposing the cell toward cancer progression. Through the application of genome-wide gene knockout screening in HPV+ HNSCC cells, we have revealed several factors which disrupt the normal cellular epigenetic landscape. Among them were the lysine acetyltransferase 2A (KAT2A) and members of the polycomb repressor complex 2 (PRC2). Interestingly, PRC2 is part of an evolutionarily conserved mechanism known to contribute to cancer immune evasion and resistance to immunotherapies by downregulation of the major histocompatibility complex I (MHC-I). We validated our screening results with additional genetic knockouts and identified multiple small molecule inhibitors that may help remediate the pathologic epigenetic changes. We have also identified novel targets within the pathway of MHC-I downregulation that we hope will aid in the development of future treatments for HPV+ HNSCC. Prior to this study, we identified a homeostatic signaling molecule, CXCL14, as a crucial antitumor factor that is epigenetically silenced in HPV+ cancer progression. Rescued CXCL14 expression in HPV+ tumor cell lines suppressed tumor growth and suggested that its restoration may help to treat some HPV+ cancers. Here we provide new developments in understanding CXCL14 antitumor properties, and we outline the development of a novel transgene therapeutic platform to further study CXCL14 antitumor immunity.
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