Schmidt, Nathalie Monika;
(2022)
Targeting cholesterol esterification as a novel immune checkpoint in viral infections and cancer.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
Identifying metabolic targets that constrain tumours and viruses while boosting exhausted, dysfunctional T cells can provide novel therapeutic checkpoints. Modulating cholesterol esterification by inhibiting the enzyme acyl-CoA:cholesterol acyltransferase (ACAT) has a direct antitumour and antiviral effect and enhances murine anti-tumour CD8+ T cells. In this thesis, I showed that reduced formation of cholesterol-rich microdomains within the cell membrane (lipid rafts) was a feature of PD-1hi exhausted CD8+ T cells. I therefore investigated the potential for rescuing exhausted human T cells by modulating cholesterol esterification and lipid raft formation. Inhibiting ACAT enhanced the expansion of functional virus- and tumour-specific T cells from donors with chronic hepatitis B virus (HBV) infection, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, and hepatocellular carcinoma. The immune-boosting effect was not limited to circulating T cells but could also enhance the function of T cells directly ex vivo from the immunosuppressive liver and tumour microenvironment in the majority of donors. ACAT inhibition led to a redistribution of intracellular cholesterol with reduced neutral lipid droplets and increased lipid raft formation, resulting in enhanced T cell receptor (TCR) signalling and T cell effector function. Additionally, ACAT inhibition induced TCR-independent bioenergetic rewiring with a skewing towards utilization of oxidative phosphorylation. ACAT inhibition had a complementary effect with other immunotherapies, with increased responsiveness to PD-1 blockade and enhanced functional avidity of TCR-engineered T cells recognizing HBV and tumour cells. Taken together, reduced lipid rafts are a feature of exhausted T cells and modulating cholesterol esterification by ACAT inhibition is a promising novel immunotherapeutic approach to boost exhausted antiviral and antitumour T cells in acute and chronic infection and in cancer.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Targeting cholesterol esterification as a novel immune checkpoint in viral infections and cancer |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2022. 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 > Div of Infection and Immunity |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10161886 |
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