UCL Discovery
UCL home » Library Services » Electronic resources » UCL Discovery

Characterisation and therapeutic harnessing of liver-resident gamma delta T cells to target hepatocellular carcinoma

Zakeri, Nekisa; (2022) Characterisation and therapeutic harnessing of liver-resident gamma delta T cells to target hepatocellular carcinoma. Doctoral thesis (Ph.D), UCL (University College London).

[thumbnail of Zakeri_Thesis.pdf] Text
Zakeri_Thesis.pdf - Other
Access restricted to UCL open access staff until 1 May 2023.

Download (42MB)

Abstract

More effective immunotherapeutic strategies are urgently needed for hepatocellular carcinoma (HCC). Gamma delta (γδ) T cells are attractive candidates for cancer immunotherapy with potential for HLA-unrestricted tumour reactivity. In this thesis, I characterise the phenotypic and functional profiles of tissue-resident memory (TRM) Vδ1 and Vδ2 T cells in human liver, examine their potential contributions to immunosurveillance in HCC, and explore therapeutic strategies to enhance the anti-tumour potential of Vγ9Vδ2 TRM cells for immunotherapy for HCC. I find that Vδ1 and Vδ2 T cells exhibit a bona fide TRM phenotype in human liver (CD69+CD49a+ and/or CD103+) with increased expression of the liver-homing chemokine receptors CXCR6 and CXCR3. Vδ1 and Vδ2 TRM cells show no egress from hepatic vasculature, demonstrate long-lived persistence in the liver for over a decade, and display superior anti-tumour cytokine production. Higher intratumoural γδ T cell counts in HCC are associated with smaller tumour size and longer patient survival. Vδ1 T cells display a more activated phenotype in HCC, while Vγ9Vδ2 T cells appear selectively depleted but maintain high IFN-γ production and equivalent capabilities to acquire an intratumoural γδ TRM phenotype. I demonstrate that intrahepatic and intratumoural Vγ9Vδ2 TRM cells efficiently target HCC cell lines (HepG2 or HuH7) sensitised to accumulate isopentenyl-pyrophosphate by the aminobisphosphonate Zoledronic acid (ZOL). In vitro expansion of blood Vγ9Vδ2 T cells using ZOL and IL-2 recapitulates a de novo TRM phenotype with enhanced cytotoxic potential. Using an in vivo murine model, adoptive cell transfer of ZOL-expanded Vγ9Vδ2 T cells combined with intratumoural ZOL sensitisation induces the greatest HepG2 tumour regression. In conclusion, intrahepatic γδ TRM cells demonstrate beneficial and long-lived immunotherapeutic properties. Future trials could explore a dual immunotherapeutic strategy using aminobisphosphonates to induce Vγ9Vδ2 TRM cells capable of replenishing the depleted pool in HCC, with additional intra-tumoral delivery of aminobisphosphonates to sensitise HCC for more efficient Vγ9Vδ2 TRM based targeting.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Characterisation and therapeutic harnessing of liver-resident gamma delta T cells to target hepatocellular carcinoma
Language: English
Additional information: Copyright © The Author 2022. 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 > 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 > Div of Infection and Immunity
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL
URI: https://discovery.ucl.ac.uk/id/eprint/10146685
Downloads since deposit
1Download
Download activity - last month
Download activity - last 12 months
Downloads by country - last 12 months

Archive Staff Only

View Item View Item