Doctor of Philosophy
Microbiology and Immunology
Mymryk, Joe S.
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.
Summary for Lay Audience
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). CESC and HNSC are the 4th and 7th most common cancers worldwide, respectively. The distinctive etiological factors that are involved in CESC and HNSC tumorigenesis—such as the expression of exogenous oncogenic viral antigens in HPV-positive (HPV+), but not HPV-negative (HPV–), carcinomas—provides us with a unique opportunity to study differences in the tumor microenvironments of HPV+ and HPV– carcinomas in 2 distinct anatomical regions. Much of the existing literature that underpins the foundation for this body of work utilizes artificial in vitro model systems. However, their lack of heterogeneity, tumor microenvironment, and infiltrating immune cells severely limit their ability to recapitulate actual human cancers. Therefore, this work capitalizes on genomic and transcriptomic “big” data acquired through next-generation “-omics” technologies from actual human tumors, which allow for an insightful elucidation of mechanistic processes under the influence of a native heterogeneous environment. Utilizing computational methods, this work explores and profiles the epigenetic and immune landscapes between the tumor microenvironments of HPV+ and HPV– carcinomas present in actual human malignancies. The studies presented in this thesis identify strikingly profound differences in the epigenetic and immune landscapes of the tumor microenvironments of these 2 etiologically-distinct carcinomas, regardless of their tissue of origin. Furthermore, they also provide insight into the validity of 2 important models of high-risk HPV-mediated sabotage of intracellular epigenetic and immune networks that were previously proposed from artificial in vitro culture studies. In addition, these studies identify potentially useful therapeutic targets and advocate for the utility of novel immunotherapy treatment modalities. Moreover, they also identify potentially predictive biomarkers of clinical outcomes that could have implications for treatment deintensification.
Gameiro, Steven F., "The Epigenetic And Immune Landscapes Of HPV+ Tumor Microenvironments" (2019). Electronic Thesis and Dissertation Repository. 6700.
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