Robert De Massy, Marc Louis;
(2021)
Features of the intratumoral T cell receptor repertoire associated with antigen exposure in cancer patients.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
The clinical success of immunotherapies demonstrates the importance of the immune system in tumour control, but the response rates remain low and many biological mechanisms underlying how these therapies work are still uncharacterised. In particular, the specificity of the anti-tumour immune response pre-existing in treatment-naive patients or induced by treatment remains poorly described. In this thesis, I explore how T cell receptor (TCR) sequencing data in multi-omics contexts can be utilised to identify features associated with antigen exposure in cancer patients. In treatment-naive non-small cell lung cancer (NSCLC) patients, multi-region TCR sequencing revealed a pattern of heterogeneity in the TCR repertoire resembling the heterogeneity observed in the mutational profile of these tumours and a range of clonotype frequency values associated with tumour specificity. A novel method was built in order to identify distinct TCR populations that spatially follow the pattern of the well-established clonal/subclonal mutational dichotomy. The impact of immune checkpoint blockade therapy on the TCR repertoire distribution was assessed in advanced renal cell carcinoma in the context of anti- PD1 treatment. TCRs with frequency distribution characteristics similar to what was observed in NSCLC were maintained upon treatment and associated with clinical response. In addition, RNA-sequencing analysis identified a gene expression profile consistent with specific activation of T cells through TCR signalling. Finally, the same methodology was applied to bone marrow samples harvested from B cell acute lymphoblastic leukaemia (B-ALL) patients. A statistical framework was developed in order to efficiently distinguish leukaemic re-arrangements from the non- leukaemic TCR repertoire of B-ALL patients. Subsequently, longitudinal analysis revealed TCR distributions that suggested the presence of cytotoxic T cells which was further characterised in matched single-cell RNA sequencing data.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Features of the intratumoral T cell receptor repertoire associated with antigen exposure in cancer patients |
| Event: | UCL (University College London) |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2021. 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 Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10134324 |
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