The Epigenetic And Immune Landscapes Of HPV+ Tumor Microenvironments

Human papillomaviruses (HPVs) are responsible for approximately 4.5% of the global cancer burden. Virtually all cervical cancers (CESC) are caused by HPVs, as well as a subset of head and neck squamous cell carcinomas (HNSC). Our studies began by using data from over 800 CESC and HNSC samples from The Cancer Genome Atlas (TCGA) to test a model proposed from in vitro studies of an HPV-dependent deregulation of the cyclin-dependent kinase inhibitor 2A(CDKN2A) locus. Similar to the proposed models, we found that the HPV+ TMEs—regardless of tissue of origin—expressed significantly higher levels of KDM6A which demethylates the repressive tri-methylated lysine 27 on histone 3—critical for tightly regulating expression from the aforementioned locus. Furthermore, we also found that CpG methylation of the CDKN2A locus was consistently altered in HPV-positive (HPV+) tumors. We next wanted to test another in vitro model that proposed an HPV-dependent transcriptional downregulation of genes that encode for essential products of the class I major histocompatibility complex I (MHC-I) antigen presentation system. Utilizing the same large TCGA cohorts, we unexpectedly found that these genes were expressed at high levels in HPV+ tumors. The high mRNA levels of the MHC-I antigen presentation apparatus could be a consequence of the higher intratumoral levels of interferon-gamma (IFNγ) observed in HPV+ carcinomas, which correlated with signatures of increased infiltration by T- and NK-cells. In addition, we also found increased expression of the class II MHC antigen presentation system in HPV+ HNSC. Furthermore, we observed that HPV+ HNSC TMEs exhibited a strong bias towards a Th1 response which was characterized by increased infiltration with multiple types of immune cells and expression of their effector molecules. Moreover, the HPV+ HNSC TME also expressed high levels of multiple T-cell exhaustion markers that were indicative of a T-cell-inflamed phenotype. Overall, these analyses have provided significant insight into the validity of models proposed from experiments conducted in relatively artificial in vitro culture systems. Importantly, these studies have illustrated, in great detail, the strikingly profound differences in both the epigenetic and immune landscapes between the tumor microenvironments of HPV+ and HPV-negative carcinomas