Correlative and functional analysis of genomic instability and immune response in colorectal and endometrial cancer

Thesis

Cancer is a common disease, which results in considerable amounts of morbidity and mortality worldwide. It is now recognised that the tumour immune response is essential in determining cancer biology. However, anti-tumour immunity varies considerably between cancers, and even within the same cancer type. In part, it is determined by the tumour mutational landscape. But much remains to be understood about how the interaction with the cancer genome shapes the tumour immune microenvironment, and influences clinical outcomes.

In this research, I demonstrated that tumour CD8+cell infiltrate is significantly associated with reduced recurrence risk and improved overall survival in stage II/III colorectal cancer (CRC). Importantly, this relationship was independent of key confounding factors, including genomic instabilities that have been shown to influence both anti-tumour immunity and clinical outcomes. Furthermore, this relationship was not consistent across all stage II/III CRCs, but rather varied according to tumour and nodal status. Mismatch repair deficiency (MMRd) is a form of genomic instability that contributes to the development of both CRC and endometrial cancer (EC). I showed that MMRd is associated with improved outcomes in CRC, but not EC. This might be a reflection of differences in the immune landscape between MMRd CRC and EC: MMRd CRCs had much greater levels of infiltrate T lymphocytes. Furthermore, MMRd ECs showed an enrichment for loss of function JAK1 mutations, which was associated with abrogated IFNγ signalling activation. Finally, this research demonstrated a murine model to allow functional investigation of MMR loss and its impact on the tumour microenvironment. Conditional, inducible Mlh1 loss resulted in a specific phenotype, with the development of intestinal polyps. In contrast to human disease, these polyps showed CD8+ T cell exclusion, which may be a secondary to Beta-2 Microglobulin loss.

In summary, this work constitutes a correlative and functional study of the associated between the immune response and clinical outcome, and how the this is influenced by tumour genomic instability.

Authors: Glaire, M

• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: T-cell; clinical outcome; immune response; colorectal cancer
• Subjects: Colorectal cancer; Immunology; Cancer