Immunomodulation within the head and neck tumour microenvironment

Murray, Patrick Francis

April 2014

Thesis or dissertation

© 2014 Patrick Francis Murray. All rights reserved. No part of this publication may be reproduced without the written permission of the copyright holder.

Changes in the immune response have been implicated in the progression of squamous cell carcinoma of the head and neck (HNSCC). Evidence is emerging that processes within the tumour microenvironment can lead to immune modulation and subsequent tumour growth or metastasis.

The hypothesis of this thesis is that the HNSCC tumour microenvironment will have increased levels of cytokines that produce an overall negative effect on the cellular cytotoxic immune response against the malignant cells. Specifically, it is hypothesised that a Th-2-like anti-inflammatory response will favour tumour cell progression and be associated with advanced stage HNSCC.

This thesis examines the levels of a panel of immune cytokines to investigate whether difference in these levels have an association with the progression of the disease and other standard clinico-pathological factors. A method of protein extraction from tumour tissue and detection of quantitative cytokine levels was developed and optimised. A cohort of 69 patients newly-presenting with HNSCC was recruited prospectively to the study, with a total of 83 samples of primary HNSCC tumour tissue and metastatic nodal tissue being investigated.

Increased levels of TGF-β, described as concentration of cytokine/mg total protein extracted, (median 1051 pg/mg vs. 659 pg/mg, p= 0.004) and reduced levels of IL-17 (median 4.2pg/mg vs. median 18.6 pg/mg, p= 0.009), compared with normal tissue from control patients were reported. The HNSCC samples were also found to have higher levels of VEGF in tumour samples (83 pg/mg vs. 27.6 pg/mg, p=0.026) compared with control tissue. No difference was found in the levels of IL-2, IL-10, IL-12, IL-15, or IL-17. When comparing early stage (I-III) to late stage IV HNSCC patients it was found that there were significantly lower levels of the Th1-like IL-12 in the higher stage IV patients (median 50pg/mg vs. 21 pg/mg, p= 0.01), and significantly higher levels of IL-15 in stage IV patients (median 52 pg/mg, vs. 20 pg/mg p= 0.03).

In summary, analysis of cytokine levels within the tumour microenvironment of HNSCC may be of prognostic value, and further study of the immune suppressive nature of HNSCC could open potential therapeutic approaches, especially if such data are correlated with other cellular parameters, e.g. T regulatory or CD8+ve T cell levels.

Postgraduate Medical Institute, The University of Hull
Greenman, John (Professor of tumour immunology); Stafford, Nicholas
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