Mitigating the impact of COVID-19 in the United Kingdom through data to safeguard patients with cancer and an immunogenomic analysis of colorectal cancer

Starkey, Thomas ORCID: 0000-0002-6692-9563 (2024). Mitigating the impact of COVID-19 in the United Kingdom through data to safeguard patients with cancer and an immunogenomic analysis of colorectal cancer. University of Birmingham. Ph.D.

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Abstract

An immunogenomic analysis of colorectal cancer:

Anti-tumour immune responses in colorectal cancer (CRC) have been defined in the context of immune cell infiltration and checkpoint regulation. However, functional immunogenomic changes and interplay with other features of CRC biology have not been fully described. I performed transcriptomic immune expression profiling in CRC primary tumours, pre-CRT treatment rectal cancers, local lymph node metastases and adjacent normal tissue, and secondary liver metastases and lung metastases. This included developing a pipeline analysing the Cancer Immunity Cycle and cancer antigen presentation characterised using validated gene sets, with immune expression profiles subsequently compared to other CRC features. I observed enrichment of functional immune gene sets defining immune cell infiltration into tumours and cancer cell killing in microsatellite instability and right-sided CRC tumours. Cancer antigen presentation signatures were highly expressed in rectal cancers with good CRT responses and expression within lymph nodes associated with early-stage CRC tumour proliferation and aggressiveness, corresponding with clinical outcomes. Higher tumour-infiltrating lymphocyte expression, driven by increased MHC Class II antigen presentation and cDC1 dendritic cell expression activity, was observed in CRC lung metastases. Better understanding immune functionality underlying anti-tumour responses is important for identifying CRC patients with increased risk of CRC tumour recurrence/metastasis and may elucidate novel targets for immunotherapy.

Mitigating the impact of COVID-19 in the UK through data to safeguard patients with cancer:

Individuals with a cancer diagnosis were reported to have poor clinical outcomes associated with COVID-19. following infection. However, cancer is a heterogeneous group of diseases and studies assessing individual risk, and benefits of COVID-19 vaccines, had not previously been performed using population-level data. I evaluated COVID-19 disease phenotype in patients with cancer compared to the general population and within cancer subgroups in 2020 and over the course of the pandemic, assessing the effects of cancer features and demographics, and determining the efficacy of vaccines from SARS-CoV-2 antigen and antibody testing data. An acute COVID-19 disease phenotype was observed in patients with cancer in 2020 but became less severe over the course of the pandemic. COVID-19 vaccines provided effective protection against infections, severe disease, and COVID-related mortality for many patients with cancer. However, individuals with cancer show lower levels of vaccine protection and more rapid waning, reduced post-vaccine antibody responses, and remain at higher risk of COVID-19 hospitalisation and death compared to the general population. Individuals with haematological malignancies had the lowest level of vaccine protection and poorest post-COVID-19 outcomes. The overall impact of COVID-19 is heterogeneous but individuals with cancer still require protection from being exposed to COVID-19.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):