Phenotypic and functional characterisation of regulatory T cells in head and neck squamous cell carcinoma

Drennan, Samantha

March 2013

Thesis or dissertation

© 2013 Samantha Drennan. All rights reserved. No part of this publication may be reproduced without the written permission of the copyright holder.

Head and neck cancer is the sixth most common cancer worldwide. Despite advances in therapy, the five year survival rate remains poor. The presence of regulatory T cells (Tregs) may be a mechanism by which head and neck squamous cell carcinoma (HNSCC) evades the immune system. Using flow cytometry to identify distinct Treg populations on the basis of phenotype and a CFSE proliferation assay, the frequency and suppressive activity of Treg populations from the peripheral circulation and tumour microenvironment of newly-presenting HNSCC patients was assessed. No difference in the circulating Treg prevalence was observed between HNSCC patients (n=39) and healthy controls (n=14), or between patients with HNSCC from different subsites. However, patients with advanced stage tumours and those with nodal involvement had significantly elevated levels of peripheral CD4+CD25highCD127low/- Tregs compared with patients who had early stage tumours (p=0.03) and those without nodal involvement (p=0.03) respectively. Circulating CD4+CD25highCD127low/- Tregs from the entire HNSCC patient cohort and patients whose tumours had metastasised to the lymph nodes suppressed the proliferation of effector T cells significantly more compared with those from healthy controls (p=0.04) or patients with no nodal involvement (p=0.04). Additionally, peripheral CD4+CD25interCD127low/- Tregs consistently induced greater suppressive activity than CD4+CD25highCD127low/- Tregs. The tumour microenvironment had an elevated frequency of Tregs (p≤0.002) and a lower frequency of effector T cells (p≤0.03) compared with the patient's peripheral circulation (n=15). No difference was observed in the level of suppression between tumour and peripheral Tregs. Using immunohistochemistry, patients with oropharyngeal tumours showed a significantly greater infiltration of Foxp3+ cells in the tumour and stroma compared with laryngeal tumours. Furthermore, as determined by ELISA, the dispersed tumour specimens secreted detectable levels of TGF-β and IL-10, but secretions from HNSCC (dissociated tumour samples and cell lines) did not influence the suppressive activity of Tregs. Clarifying the role of CD127low/- Tregs in HNSCC and the influence the tumour may have on the regulatory population will provide the opportunity, through future work, to establish whether Tregs can be used as a prognostic determinant or manipulated by immunotherapy.

Hull York Medical School, The University of Hull and the University of York
Green, Victoria L.; Stafford, Nicholas
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