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Investigating the role of TIM3 in regulating the tumour-specific CD8 T-cell response using a 3D tumour spheroid model.

Wong, Carissa 2021. Investigating the role of TIM3 in regulating the tumour-specific CD8 T-cell response using a 3D tumour spheroid model. PhD Thesis, Cardiff University.
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Abstract

Within the solid tumour microenvironment (TME), immunosuppressive mechanisms limit the cytotoxic potential of tumour-specific CD8 T-cells, including the ligation of coinhibitory receptors expressed on tumour-infiltrating lymphocytes (TILs). TIM3 is a receptor that is highly expressed on exhausted CD8 TILs in the TME and has been described to transmit both costimulatory and coinhibitory signalling. However, contextual regulators of TIM3 signalling are unclear. Additionally, it is unknown to what extent the therapeutic effects of TIM3 blockade, commonly observed in preclinical models, are mediated by direct blockade of TIM3 signalling on CD8 T-cells or other cell types which indirectly promote the anti-tumour CD8 T-cell response. Using reductionist in vitro 2D monolayer and 3D tumour spheroid models of murine renal carcinoma (Renca) and primary CD8 T-cells from neoantigen-specific TCR transgenic mice, the context-dependent role of TIM3 in directly regulating the antigenspecific cytotoxic CD8 T-cell response was investigated. TIM3 overexpression by CD8 Tcells inhibited T-cell cytotoxicity within the 3D Renca model, in a manner reversible by TIM3 blockade. In contrast, TIM3 overexpression enhanced IFNγ secretion and slightly enhanced cytotoxicity by CD8 T-cells within the 2D Renca model, in a manner unaffected by TIM3 blockade. Using overexpression of a truncated form of TIM3 on CD8 T-cells, these divergent effects were found to be dependent upon the TIM3 cytoplasmic tail. TIM3 overexpression enhanced the ability of CD8 T-cells to form cell couples with 2D Renca cells and the interface stability within cell couples. CEACAM1, a putative TIM3 ligand, was found to abrogate both TIM3-dependent CD8 Tcell suppression in the 3D Renca model and TIM3-dependent CD8 T-cell stimulation in the 2D Renca model, when overexpressed by CD8 T-cells in cis with TIM3. CEACAM1 overexpression in trans by Renca tumour target cells inhibited T-cell cytotoxicity in the tumour spheroid and monolayer models, in a manner dependent and independent of TIM3, respectively.

Item Type: Thesis (PhD)
Date Type: Completion
Status: Unpublished
Schools: Medicine
Date of First Compliant Deposit: 26 January 2022
Last Modified: 27 Jan 2022 10:34
URI: https://orca.cardiff.ac.uk/id/eprint/146910

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