The effects of hypoxia on the anti-tumour immune response

Thesis

Hypoxia is an adverse prognostic feature in cancer, conferring resistance to treatments including immunotherapy. In this thesis, image analysis of human tumour histology samples and murine models is utilised to evaluate some aspects of the interactions between tumour oxygenation, cellular oxygen sensing and immunity.

In Chapter 1, a novel image analysis pipeline is validated and utilised to analyse the distribution, relative to hypoxia, of tumour infiltrating leukocytes in pimonidazole-treated head and neck squamous cell carcinomas before comparing the observed distributions to those in clear cell renal cell carcinoma, a tumour characterised by perturbed oxygen sensing. Leukocyte-specific distribution patterns were shared by both tumour types, with lymphoid cells largely restricted to better oxygenated perivascular regions and myeloid cells being more diffusely distributed including within profoundly hypoxic necrotic regions.

In Chapter 2, this pipeline is used to evaluate immunohistochemically labelled hypoxia, vascular and immunological markers in lung cancer samples from participants in a clinical study evaluating whether atovaquone, an oxidative phosphorylation inhibitor, reduces tumour hypoxia. Although scoring of all markers was equivalent between groups, given that atovaquone-treated tumours were more hypoxic at baseline, this may represent a meaningful finding.

Chapter 3 concerns histological phenotyping of transgenic mice in which hypoxia-inducible factor (HIF) was up-regulated through reversible prolyl hydroxylase domain-containing protein 2 (Phd2) gene silencing, leading to regulatory T lymphocyte dysfunction and autoimmunity.

Given that regulatory T lymphocytes suppress anti-tumour immunity, in Chapter 4, the effects of host Phd2 silencing are assessed in murine tumour models. Disappointingly, this intervention affected neither tumour growth nor immune contexture.

Authors: Macklin, P

• DOI: 10.5287/ora-azymneann
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Subjects: Immunity; Cancer; Oxygen