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).

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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.

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