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Human γδ T-APCs: processing of tumour antigens and induction of anti-tumour immunity

Rus, Teja 2021. Human γδ T-APCs: processing of tumour antigens and induction of anti-tumour immunity. PhD Thesis, Cardiff University.
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γδ T cells play an important role in cancer immune surveillance. In vitro expanded Vγ9/Vδ2 T cells retain their cytotoxic potential and functionality as assessed by their cytokine secretion (IFNγ and TNFα) and proliferation responses to phosphoantigens (pAgs). Notably, upon activation, Vγ9/Vδ2 T cells act as professional APCs (γδ T-APCs), capable of processing simple and complex microbial antigens, and inducing responses in CD4 and CD8 αβ T cells. However, their capacity to process tumour antigens and to induce anti-tumour T cell responses remain poorly understood. Here, the methods for generating tools necessary to study the processing and cross-presentation in Vγ9/Vδ2 T cells are described. Namely, I have optimised a method for purification of recombinant tumour antigen NY-ESO-1 in a single chromatography step and established a protocol for expression and purification of recombinant 5T4 antigen from the bacterial system. Furthermore, I describe a method for the generation of functional 5T4 specific CD8 T cells within 4-6 weeks, which may be used for the generation of other “difficult”, self-antigen reactive CD8 T cell clones and lines. Importantly, I discuss a novel protocol for the generation γδ T-APC with an optimal phenotype. My findings demonstrate that briefly stimulated Vγ9/Vδ2 T cells, but not expanded Vγ9/Vδ2 T cells, become robust pro-APCs, capable of cross-presenting tumour antigen and inducing moderate IFNγ responses in cognate CD8 T cells. Results presented here suggest that γδ T-APCs as well as expanded Vγ9/Vδ2 T cells readily take-up parts of cancer cells for processing and successfully cross-present tumour antigen. The data show that zoledronate or γ-radiation-sensitised cancer cells enhanced the APC phenotype and function in expanded Vγ9/Vδ2 T cells. Sensitised cancer cells induced expression of CD36 scavenger receptor involved in endocytosis of extracellular material. Further studies are required to confirm receptors/signalling involved in these processes. In conclusion, my findings confirm that γδ T-APCs are indeed capable of efficient cross-presentation of tumour antigens (5T4). Further studies are required to expand these findings to other types of tumour antigens (such as NY-ESO-1) and in vivo tumour models. As evidenced by my in vitro studies and previously reported findings, γδ T-APCs show great potential in cancer immunotherapy. The ease of efficient ex vivo expansion, safety, and robust antigen-presenting capability makes Vγ9/Vδ2 T cells a promising alternative to dendritic cells.

Item Type: Thesis (PhD)
Date Type: Completion
Status: Unpublished
Schools: Medicine
Date of First Compliant Deposit: 15 September 2021
Last Modified: 15 Sep 2021 12:44

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