This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Oncogenic viruses are etiologic agents in two forms of head and neck cancer: Epstein-Barr virus (EBV) associated undifferentiated nasopharyngeal carcinoma, and human papillomavirus (HPV) associated oropharyngeal squamous cell carcinoma (OSCC). We previously discovered that EBV transactivates a human endogenous retrovirus, HERV-K18, that encodes a superantigen in its env gene. Superantigens cause strong T cell activation and cytokine production, resulting in inflammation. Recently, we found that HPV also induces this superantigen in epithelial cells, suggesting a possible etiological role for HERV-K18 in virally associated head and neck cancers. In support of our findings, superantigen transcripts were significantly increased In HPV+ OSCC compared with HPV- tumors. Our central hypothesis is that HERV-K18 superantigen activated T cells affect virally associated head and neck cancers, by eliciting a localized inflammatory response that could either promote or inhibit carcinogenesis, depending upon the T cells present in the tumor microenvironment. Superantigen associated T cell proliferation could result in expansion of either effector or regulatory responses, while activation induced cell death could result in a functional state of tolerance of particular T cell subsets. This could promote tumorigenesis by amplifying T regulatory or suppressive responses, providing growth factors and chemokines that recruit cells, angiogenic factors and matrix metalloproteases, all of which would advance metastasis. Disrupting the superantigen activated T cell response in that case might prevent metastases. Conversely, superantigen activation has the potential to inhibit tumorigenesis, by expanding cytotoxic T cells, which would enhance immunosurveillance. In which case, exploiting the superantigen mediated cytokine response might have therapeutic benefit. In the original proposal, we aimed to: (1) model and characterize HERV-K18 superantigen mediated T cell responses to HPV+ vs HPV- OSCC;(2) perform microarray and cytokine array studies on HPV+ vs HPV- OSCC stratified for HERV-K18 expression; (3) Develop agents that inhibit or induce HERV-K18 superantigen presentation and characterize their effects on T cell function;(4) Measure therapeutic efficacy of agents that inhibit or induce HERV-K18 superantigen activated T cells in a xenograft mouse tumor model. By characterizing superantigen T cell responses, we expect to identify immunomodulatory mechanisms at play in HPV associated head and neck tumors, with the ultimate goal of potentiating anti-tumor immunity. The proposed studies would allow us to explore the role of superantigen activated T cells on viral carcinogenesis, and suggest immunological methods for preventing tumor progression, possibly identifying new treatment options. However, this application was awarded only limited bridge funding of $20,000, for one year, non-renewable. Since the full proposal could not be completed under such budget and time constraints, we concentrated on specific aim 2, performing cytokine and gene expression microarray analyses on tissue specimens from patients with HPV+, HERV-K18+ vs. HPV-, HERV-K18- tumors.
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