Peakman, Frederick Mark;
(2021)
Exploring neutrophil heterogeneity in health and cancer.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
Interactions between cancer cells and their microenvironment are critical for tumour initiation, growth and metastasis. Consequently, a greater understanding of these interactions may offer novel opportunities for therapy. Neutrophils are innate immune cells that form a component of the tumour microenvironment. Both pro- and anti-tumour effects of neutrophils are reported in the literature, suggesting context-dependent complexity in neutrophil-tumour interactions. This complexity is further deepened by recent reports demonstrating that neutrophil populations are more heterogeneous than previously appreciated, but it is unclear what significance this may have in a cancer context. This thesis therefore aimed to investigate how tumours perturb neutrophil heterogeneity and the potential functional consequences of this perturbation for neutrophiltumour interactions. I first used mass cytometry to perform high-dimensional analysis of mouse neutrophil surface marker expression across tissues and control and tumour-bearing contexts, using the MMTV-PyMT mouse model of breast cancer. This revealed a number of neutrophil populations defined by their differential expression of surface markers, with shifts in the populations observed between control and tumour-bearing mice. In particular, a population of neutrophils defined by low expression of L-Selectin (CD62L- ) expands in the bone marrow, circulation and periphery of tumour-bearing mice. This phenotype was observed in a number of other mouse cancer models. Analysis of nuclear morphology found that CD62Lneutrophils have a more hyper-segmented nucleus than CD62L+ neutrophils, suggesting potential functional differences between these populations. However, a range of functional assays did not identify differences between the two populations. Instead, comparison of the total neutrophil population from control mice and tumour-bearing mice discovered differences in functionality. Most significantly, when comparing neutrophils from control and tumour-bearing mice I found changes in kinase activity, reactive oxygen species and in vitro interactions with cancer cells, indicating broad shifts in neutrophil phenotype during the switch from a healthy state to cancer.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Exploring neutrophil heterogeneity in health and cancer |
| Event: | UCL (University College London) |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2020. Original content in this thesis is licensed under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) Licence (https://creativecommons.org/licenses/by/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 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.ucl.ac.uk/id/eprint/10119163 |
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