Hessey, Sonya; (2024) Tumour evolution and immune evasion in lung cancer from diagnosis to death. Doctoral thesis (Ph.D), UCL (University College London).

Text Sonya_Hessey_21032706_thesis_corrections.pdf - Submitted Version Access restricted to UCL open access staff until 1 May 2025. Download (29MB)

Abstract

Metastasis is a grave step of cancer progression in which tumour cells spread from their original site to a secondary location. By making localised disease systemic, metastasis accounts for the greatest cause of cancer-related mortality. The migration of tumour cells is a transient event that proves difficult to monitor in real time, however, a retrospective view of this process can be gleaned by tracking the evolutionary history of subpopulations of tumour cells, or clones, in primary tumours and metastases using DNA sequencing data. This thesis leverages longitudinally collected, multi-region primary and multi-site metastasis sequencing data from patients with non-small cell lung cancer (NSCLC) to reconstruct the sequence of events between diagnosis and death with the aim of elucidating the processes that drive metastatic progression. Marked genetic divergence between primary tumours and metastases as well as between individual metastases was observed, consistent with ongoing evolution after metastatic seeding. Metastasis genomes were characterised by putative driver mutations predominantly acquired early in tumour evolution and somatic copy number alterations accumulated in a stepwise manner throughout the disease course. Metastasis clones seeded metastases as frequently as primary tumour clones, indicating metastases are key source of metastatic progression in NSCLC. The number and location of metastases seeded by each tumour clone varied, in keeping with a context dependent spectrum of metastatic potential. Primary tumours with high somatic copy number heterogeneity harboured more seeding clones and whole genome doubling was enriched in tumour clones capable of seeding extrathoracic metastases, implicating chromosomal instability as a mediator of metastatic potential. Finally, assessment of the role of anti-tumour immunity on the metastatic process demonstrated that primary tumour immune infiltrate, antigenicity, and immune evasion capacity dictate the extent to which immune selective pressures shape metastasis evolution and immunotherapy resistance. This thesis advances the current understanding of the events and the mediators of metastasis in NSCLC, which is a key step toward improving the poor prognosis associated with this disease.

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