Dissertation

Tumour immunity and mhc class i associated phosphopeptides

Penny, Sarah Amy

2014

Overview

Immunotherapies signify a major development in the fight against increasing cancer morbidity and mortality. However, they have been limited by a lack of tumour-specific targets. MHC class I associated phosphopeptides represent a novel class of potentially tumour-specific targets, since dysregulation of signalling in cancers leads to aberrant phosphorylation. Using an autologous model of cancer, in healthy individuals, it was shown that a significant proportion of all anti-tumour cytotoxic memory T cell responses target phosphopeptides. In colorectal cancer (CRC), there is an established association between memory CD8+ T cell infiltration and survival. CRC and oesophageal adenocarcinoma tumours and cell lines were used to identify 134 tumour-associated phosphopeptides. Approximately 65% of these derive from well-defined cancer pathways and are thus markers of malignancy. Multifunctional tumour-infiltrating lymphocytes were present in primary and metastatic tumours that recognised these phosphopeptides. Furthermore, healthy donors have pre-existing memory T cell responses to many CRC-associated phosphopeptides. Phosphopeptide-specific T cells were readily expanded ex vivo and killed CRC cell lines. Therefore, MHC class I associated phosphopeptides are ideal immunotherapeutic targets, as immunity must spare healthy tissue. Immunity to tumour-associated phosphopeptides represents a biological strategy for distinguishing tumour from healthy tissue. These phosphopeptides are potential sHLA-associated cancer biomarkers and immunotherapeutic targets.

• Publisher: ProQuest Dissertations & Theses