Southern Navarrete, Alba; (2025) Enhancing γδ T cell homing and persistence towards osteosarcoma. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Gamma delta (γδ) T cells have demonstrated to be a promising cellular therapy approach, possessing innate anti-tumour activity, potent antibody-dependent cytotoxicity (ADCC) and minimal alloreactivity. Vγ9Vδ2 T cells are the predominant subset in the peripheral blood, which can be indirectly activated by a class of synthetic drugs called nitrogen containing bisphosphonates such as zoledronic acid (ZOL), a compound which preferentially binds to the bone. Despite the therapeutic promise, the clinical applications of Vγ9Vδ2 T cells face challenges, particularly in their persistence, survival and ability to infiltrate and home into the complex tumour microenvironment of solid tumours. This work aimed to address these obstacles by using gene engineering advancements to enhance the efficacy of Vγ9Vδ2 T cells against solid tumours, with a focus on osteosarcoma (OS). We showed that engineering Vγ9Vδ2 T cells to overexpress a C-X-C chemokine receptor type 6 (CXCR6, a receptor whose ligand is expressed by human OS cancer cells) and to secrete a mitogenic IL-15Rα–IL-15 fusion protein (stIL15) enhanced the persistence and homing to 2D and 3D OS models. The production of stIL15 prevented collapse upon withdrawal of exogenous cytokine support, however, promoted a decrease in CXCR6 expression and minimal directional migration towards its ligand CXCL16. Transduction of stIL15-Vδ2 T cells to enhance CXCR6 expression enhanced directional migration towards its ligand, as well as OS cells and supernatants, in 2D and 3D models. Moreover, the combinatorial treatment of stIL15-CXCR6-Vδ2 T cells with ZOL promoted a chemotactic environment enhancing infiltration, persistence and cytotoxicity in 3D models. In vivo, engineered Vδ2 T cells were visualised in the OS microenvironment after 14 days of administration, proving their persistence and homing to the tumour. Taken together, Vγ9Vδ2 T cells that secrete stIL15 and are armoured with tumour-specific chemokine receptors can represent a promising strategy for allogeneic cell therapies.

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