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Targeting therapeutic T cells to the bone marrow niche

Khan, Anjum Bashir; (2019) Targeting therapeutic T cells to the bone marrow niche. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

Anti-cancer immunotherapies aim to mediate a specific response targeting malignant cells without accompanying damage to normal tissue associated with conventional therapies, but induction of T cell differentiation and exhaustion enables successful tumour progression. In this thesis I will explore different means of enhancing the accumulation and function of therapeutic CD8 T cells, as a means of achieving functional cure through persisting immunological memory. I will show that the key features of T cell memory can be imprinted upon CD8+ T cells by enhancing homing to specific organs, enabling privileged access to cell-mediated factors. The interaction between the chemokine receptor CXCR4 and the ligand CXCL12/SDF-1 is required for successful homing of haematopoietic stem cells (HSCs) to stromal niches within the bone marrow (BM). The bone marrow is known to be a unique organ for immunological memory, including memory T cells. I hypothesised that replicating this bone marrow homing interaction in CD8+ T cells would preferentially generate memory T cells. I demonstrate through in vivo imaging and flow cytometric analyses that T cells over-expressing CXCR4 accumulate preferentially in the BM near vascular-associated CXCL12+ cells, retain a less differentiated central memory phenotype despite repeated antigenic stimulation, and produce enhanced effector cytokines on restimulation. Compared to control T cells, these cells demonstrate lower expression of exhaustion and senescence markers, suggesting the capacity for long-term persistence after activation. I go on to show that numerical accumulation and many of these functional attributes are dependent upon cell-extrinsic expression of IL-15Rα. TCXCR4 demonstrate heightened graft-versus-tumour effects in allogeneic bone marrow transplant models of B-cell lymphoma in comparison to control T cells. I provide evidence that this anti-tumour effect is mediated by enhanced functional capacity rather than numerical accumulation or out-competing immunosuppressive populations. In summary, this strategy offers a tractable means of enhancing T cell engraftment, persistence and function, with potential for cross-platform therapeutic applications including anti-cancer immunotherapy.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Targeting therapeutic T cells to the bone marrow niche
Event: UCL (University College London)
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Copyright © The Author 2019. 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.
Keywords: T cells, CXCR4, Bone marrow niche, Immunotherapy, Central memory T cells
UCL classification: 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 Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
URI: https://discovery.ucl.ac.uk/id/eprint/10068217
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