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Engineering homing properties of cancer-specific T lymphocytes in adoption cell therapy

Moon, Owen Rhys 2020. Engineering homing properties of cancer-specific T lymphocytes in adoption cell therapy. PhD Thesis, Cardiff University.
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Several cancer immunotherapies harness the ability of CD8 T cells to eradicate tumours. Adoptive cell transfer of cancer-specific T cells is an immunotherapy that has produced promising results for cancer patients. L-selectin is a membrane protein that enables T cell rolling on high endothelial cells and transendothelial migration into lymph nodes. During this process, and after T cell activation, the L-selectin ectodomain is proteolytically cleaved from the T cell surface by ADAM17. In preclinical melanoma models, adoptively transferred cancer-specific T cells, which expressed ectodomain shedding-resistant L-selectin, better controlled tumour growth than T cells bearing wildtype L-selectin. However, these adoptively transferred T cells were naïve and transgenic for a cancer-specific TCR and variants of L-selectin. This is a situation not reflected in the clinic. Here, I delivered a cancerspecific TCR, and variants of L-selectin, to T cells using a clinically relevant method. I further demonstrated that modified L-selectin variants affected CD8 T cell expression of CD25, Ki67, and PD-1 during cytolysis assays. A lack of L-selectin ectodomain shedding has also been implicated in degranulation and killing by effector T cells, as well as naïve T cell activation-mediated upregulation of CD25 and consequent T cell proliferation. Recently, we demonstrated that ADAM17-dependent L-selectin ectodomain proteolysis generates a membraneretained fragment (MRF) that undergoes γ-secretase proteolysis. The intracellular domain, or tail, of L-selectin interacts with several proteins, including PKC, grb-SOS, and lck. Therefore, the L-selectin tail may perform signalling functions prior to, and following, γ-secretase proteolysis in T cells. I demonstrated that the MRF of Lselectin is lost from the cell membrane, either through degradation by the proteasome or further proteolysis by γ-secretase. Therefore, the altered phenotypes conferred by shedding-resistant L-selectin to cancer-specific T cells are likely due to retention of the tail of L-selectin at the cell surface and continued interaction with binding partners.

Item Type: Thesis (PhD)
Date Type: Completion
Status: Unpublished
Schools: Medicine
Date of First Compliant Deposit: 11 January 2021
Last Modified: 07 Jan 2022 02:30

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