McJannett, Nicola Jane (2025). Optimising CAR-T cells for enhanced activity in the tumour microenvironment. University of Birmingham. Ph.D.
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McJannett2025PhD.pdf
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Abstract
Acute myeloid leukaemia is a cancer of the myeloid cells in the bone marrow. AML alters the bone marrow niche, creating an immunosuppressive microenvironment. AML increases tryptophan metabolism and cystine uptake. T-cells require sufficient nutrients to function. Due to a lack of clinical activity, CAR T-cell therapies are currently only used in a limited number of cancers. We hypothesised that the lack of nutrients in the AML microenvironment supresses CAR T-cell function.
This work discusses how the availability of tryptophan and cystine affected T-cell and CAR T-cell proliferation. We designed CAR T-cells with the overexpression of tryptophan or cystine transporters, SLC7A5 and SLC7A11, respectively. We first demonstrated that the addition of SLC7A5 and SLC7A11 to Jurkat CAR T-cells provided increased metabolic rates in low tryptophan and cystine environments, respectively. The addition of SLC7A5 and SLC7A11 to CAR T-cells increased tryptophan and cystine uptake, respectively. CAR T-cells with SLC7A5 or SLC7A11 overexpression had increased proliferation in low tryptophan and cystine environments, respectively. The CAR T-cells with overexpression of SLC7A5 and SLC7A11 improved cancer clearance in murine models. Performing RNA sequencing of CAR-T cells following interaction with tumour cells, we showed a significant alteration of pathways associated with T-cell activation, metabolism, and migration, caused by the addition of the transporters to the CAR T-cells. These results demonstrate that the addition of SLC7A5 and SLC7A11 could improve CAR T-cell function in low amino acid environments.
| Type of Work: | Thesis (Doctorates > Ph.D.) | |||||||||
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| Award Type: | Doctorates > Ph.D. | |||||||||
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| Licence: | All rights reserved | |||||||||
| College/Faculty: | Colleges (former) > College of Medical & Dental Sciences | |||||||||
| School or Department: | Institute of Immunology and Immunotherapy | |||||||||
| Funders: | Other | |||||||||
| Other Funders: | Private donation | |||||||||
| Subjects: | Q Science > Q Science (General) R Medicine > R Medicine (General) |
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| URI: | http://etheses.bham.ac.uk/id/eprint/15954 |
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