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Characterising the role of dendritic cells in TCR gene therapy

Hotblack, AC; (2017) Characterising the role of dendritic cells in TCR gene therapy. Doctoral thesis , UCL (University College London). Green open access

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Abstract

Adoptive transfer of T cell receptor (TCR) gene-modified T cells is a promising field of tumour immunology. However whilst these cells can potently control tumour growth, this occurs in only a subset of patients. In order to devise new strategies to improve the anti-tumour response we need a clear understanding of the mechanisms by which transferred T cells are activated to kill tumours. Whilst dendritic cells (DC) are required to activate and control T cell function in adaptive immune responses it is not known whether control of tumours by adoptively transferred T cells depends on similar interactions with endogenous DC. To address this the CD11c.DTR model was used to transiently deplete DC in mice with established B16.F10 sub-cutaneous tumours after having been treated with TCR-transduced T cells. Unexpectedly we found that depletion of CD11c+ cells facilitates enhanced expansion and effector-phenotype differentiation of the transferred T cells. This appears to be mediated by depletion of a DC population with regulatory capabilities. However depletion of DC in the closely related CD11c.DOG model fails to promote accumulation of TCR-transduced T cells. Indeed, in this model DC depletion leads to less T cell infiltration into tumours. These contrasting results following depletion likely reflect the heterogeneous CD11c+/DC compartment in the tumour, where different populations contribute pro- or anti-inflammatory roles. Nonetheless these data suggest that TCR-transduced T cells interact with the endogenous immune system, although the exact nature of this interaction requires further investigation.

Type: Thesis (Doctoral)
Title: Characterising the role of dendritic cells in TCR gene therapy
Event: UCL
Open access status: An open access version is available from UCL Discovery
Language: English
Keywords: Tumour Immunology, Gene therapy, Dendritic cells, Adoptive cell therapy, DC, ACT
URI: http://discovery.ucl.ac.uk/id/eprint/1537265
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