Farhat, Mustafa (2022). Study of underlying mechanisms of NK cell impairment in B-CLL patients. University of Birmingham. Ph.D.
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Farhat2022PhD.pdf
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Abstract
Despite the potent role of NK cells in eliminating the tumor and leukemic cells, NK cells in B-CLL patients are dysfunctional and impaired, which contributes to the disease progression and B-CLL patients’ mortality. NK cell impairment has been linked at least to the downregulation of activating receptors on NK cells in B-CLL patients. The first part of this study has investigated further the phenotype of NK cells and detailed functionality of NK cells from B-CLL patients. The data showed that the expression of checkpoint receptors on NK cells were significantly upregulated, including PD-1,CTLA-4, LAG-3 and CD96. Also, NK cells from B-CLL patients demonstrated reduced cytokine production and impaired DNAM-1 dependent NK cell cytotoxicity compared to age-matched healthy controls. In addition, TIGIT and/or CD96 blockades can robustly reverse the DNAM-1 dependent NK cytotoxicity against tumor cell lines. The second part of this study focused on PD-1positive NK cells. At first, scRNA-seq analysis revealed that PD-1pos NK cells have differentiated transcription profile compared to PD-1neg NK cells, which can be used to identify new potential therapeutic targets to reverse anti-tumor functions of PD-1pos NK cells. Secondly, the functionality of PD-1pos NK cells was compared with PD-1neg NK cells using primary NK cells and NK cell line models. The function of PD-1pos NK cells were significantly impaired compared to PD-1neg counterparts, including lower expression of cytokine and cytotoxicity against tumor cell lines. Interestingly, blocking of PD-1/PD-1Ls interactions have partially reversed the anti-tumor activity of PD-1pos NK cells. This study revealed for the first time that the checkpoint receptors expression on NK cells from B-CLL are upregulated and blocking PD-1 or TIGIT/CD96 receptors might be potential novel strategies for NK cell based immunotherapy for B-CLL patients.
| 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 (2008 onwards) > College of Medical & Dental Sciences | |||||||||
| School or Department: | Institute of Immunology and Immunotherapy | |||||||||
| Funders: | Other | |||||||||
| Other Funders: | Libyan Ministry of Higher Education | |||||||||
| Subjects: | Q Science > QR Microbiology > QR180 Immunology | |||||||||
| URI: | http://etheses.bham.ac.uk/id/eprint/12626 |
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