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 COHR: Center for Oral Health Research | Projects | COBRE for Oral Health - Projects - Natalie A. Sutkowski, PhD

Natalie A. Sutkowski, PhD
An Endogenous Superantigen in HPV Associated Oropharyngeal Carcinoma (Start date 8/1/08)

Overviewnatalie sutkowski

Our scientific focus is to study the interactions of viruses with the immune system, with a translational emphasis on cancer. There are two major projects ongoing in the laboratory: 1) manipulation of tumor virus immunity in carcinogenesis and in lymphomagenesis; and 2) using a novel technology we have created for development of therapeutic human monoclonal antibodies.

Abstract

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 might promote tumorigenesis by amplifying T regulatory or suppressive responses, providing growth factors and chemokines that recruit cells, angiogenic factors and matrix metalloproteases, promoting metastasis. Thus, disrupting the superantigen activated T cell response 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 this proposal, we aim 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 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. These studies should 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. In summary, this is a novel translational proposal aimed at controlling T cell responses elicited by an endogenous viral superantigen that is induced by the oncogenic virus HPV.

 

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