Does HPV-16 seropositivity correlate with T-cell distribution providing additional prognostic information in infected HNSCC patients?

Zahoor, Tosief

March 2016

Thesis or dissertation

© 2016 Tosief Zahoor. All rights reserved. No part of this publication may be reproduced without the written permission of the copyright holder.

It is widely accepted that infection with Human Papilloma Virus (HPV) confers better outcomes and survival rates in head and neck squamous cell carcinoma (HNSCC) patients (80% 5-year survival) compared with HPV-negative counterparts (50% 5-year survival),regardless of treatment modality. It is hypothesised that the increased immune response against HPV infection contributes to better survival, however the exact mechanisms involved remain unknown. The HPV oncoproteins E6 and E7 have been shown to be involved in tumourigenesis of HNSCC, particularly those originating in the oropharynx and oral cavity. These proteins appear to act through inactivating both the p53 and retinoblastoma (pRb) genes, as silencing of these viral proteins results in re-expression of these two suppressor pathways. In order to show a causative role of HPV infection and tumorigenesis a biologically active infection needs to be shown, this was done by the use of multi-modal diagnostic techniques using p16 IHC as a surrogate marker and ISH as a confirmatory test.

HPV seropositivity in HNSCC has been quoted to range between 24-67% with the exact role in prognosis not defined. HPV-oncoproteins were expressed to use against human sera in an in-house developed ELISA. This study found a high percentage of healthy controls displaying an antibody response to the HPV E7 oncoprotein, therefore the use of an antibody response as an indicator of HPV16 infection alone is not valid. However, seropositivity may be useful as a prognostic indicator when correlated with other immune markers.

Tumour infiltrating cells and CD8+ve:FoxP3 ratio have been associated with improved outcomes regardless of tumour subset. This study found TIL were higher in HPV+ compared to HPV- HNSCC and CD8+ve:FoxP3 ratio was higher in HPV positive HNSCC. CD4+ve cells are associated with increased survival outcomes, this study found high levels of CD4+ve cells associated with >3year prognosis. Improved adaptive immunity plays a role in the favourable prognosis of patients with HPV-16 positive HNSCC, further knowledge of which may lead to the development of combined targeted immunotherapy thus reducing current treatment associated morbidity, such as that associated with radiotherapy.

Hull York Medical School, The University of Hull and University of York
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