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Precision targeting of mTORC1 in tumour-specific CD4+ T cells

Sillito, Francesca Emily; (2023) Precision targeting of mTORC1 in tumour-specific CD4+ T cells. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Adoptive T cell therapies have predominantly focused on CD8+ T cells to date; however incorporation of CD4+ T cells can broaden the immune response to tumour. A potential barrier to the efficacy of anti-tumour CD4+ T cells is their phenotypic plasticity, as they may be rendered non-functional within the hostile tumour microenvironment (TME). Hence, techniques that augment the effector function of engineered CD4+ T cells are critical to their success as an anti-tumour therapy. The mammalian target of Rapamycin complex 1 (mTORC1) is a key regulator of metabolic and anabolic functions, coordinating effector differentiation and function in response to environmental stimuli. I tested the effect of overexpressing the positive mTORC1 regulator Ras homolog enriched in brain (RHEB) in a model of anti-tumour immunity that requires in vivo cytotoxic CD4+ T cell differentiation. As it has been previously found for CD8+ T cells, RHEB overexpression in CD4+ T cells enhanced glycolysis, promoted expression of T-bet and significantly increased tumour infiltration in vivo. Conversely, mTORC1 inhibition using Proline-rich Akt substrate of 40kDa (PRAS40) produced a state of relative metabolic quiescence, rendered the cells in a less differentiated Th0 state and reduced T cell infiltration of tumours. However, compared to control cells, RHEB-transduced CD4+ T cells showed reduced cytotoxic gene expression and failed to eliminate all tumours. Unlike what has been published for CD8+ T cells, constitutive mTORC1 activation did not impair long-term persistence of CD4+ T cells, but the surviving cells expressed high levels of co-inhibitory receptors (especially LAG-3) and showed impaired proliferation in response to antigenic re-challenge. Together, these data highlight the need to address how engineering of intrinsic metabolic fitness might impact upon CD4+ versus CD8+ T cells in distinct ways due to biological heterogeneity; furthermore, it suggests the need for bespoke strategies to enhance their function and survival.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Precision targeting of mTORC1 in tumour-specific CD4+ T cells
Language: English
Additional information: Copyright © The Author 2023. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/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.
UCL classification: UCL
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/10169148
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