Puttick, Clare Louise;
(2023)
Immune evasion and tumour evolution in lung cancer.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
Cancer is an evolutionary disease in which different populations of cells undergo clonal evolution. Genetic and non-genetic tumour heterogeneity plays an important role in this evolutionary process, as does selective pressure from the immune microenvironment, which can result in cancer cells acquiring immune evasion mechanisms. Disruption of the human leukocyte antigen (HLA) molecules has important implications for immune evasion and tumour evolution as a neoantigen can only elicit a cytotoxic response if it is presented to T cells by the HLA molecules. The im- pact of HLA genomic and transcriptomic disruption in non-small cell lung cancer (NSCLC) evolution remains unclear. We developed a bioinformatic tool (MHC Hammer) to quantify HLA allele-specific mutations, loss of heterozygosity (LOH), transcriptional repression and alternative splicing in a cohort of NSCLC patients. We found that just 21% (10/48) of lung adenocarcinoma (LUAD) and 7% (2/27) of lung squamous cell carcinoma (LUSC) tumours harboured no HLA LOH or tran- scriptional repression. Alternative splicing affecting HLA exons 2, 3 or 4, resulting in unstable HLA molecules unable to present neoantigens, was identified in 40% of LUAD and 26% of LUSC tumours. Alternative splicing of exon 5, yielding soluble HLA molecules, a potentially novel immune tolerance mechanism, was identified in 25% of LUAD and 22% of LUSC tumours. We also investigated clonal dynamics between pre-invasive and invasive disease in a cohort of patients with NSCLC. Two distinct modes of evolution were identified depending on whether the pre-invasive lesion and invasive tumour from a given patient descended from a somatic common ancestor (SCA) or not. By investigating the clonal dynamics in patients with a single SCA we were able to propose different evolutionary histories. Finally, the APOBEC signature was shown to occur both early and late in tumour evolution.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Immune evasion and tumour evolution in lung cancer |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2023. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10174790 |
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