Synthetic T cell receptor engagers to overcome suppression of the function of human anti-tumour T cells
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Date
2025-03-22
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Saudi Digital Library
Abstract
Cytotoxic T cells (CTL) play a key role in the tumour microenvironment (TME), as they have the ability to recognize and kill tumour target cells. Yet, that ability is largely suppressed. The suppression of CTL function is difficult to study within the entire complex TME. Therefore, we built a reductionist experimental system for the investigation of the molecular and cellular mechanism of CTL suppression in their direct interaction with tumour target cells using 3D tumour cell spheroids.
We incubated human CTL transduced to express a transgenic TCR with tumour cell spheroids in the presence of cognate antigen. This resulted in suppression of CTL function with impaired target cell killing and diminished IFN secretion. Moreover, induction of an exhaustion phenotype in spheroid-infiltrating lymphocytes was detected by the elevated frequency of the expression of suppression markers.
We also investigated the mechanism of action of a TCR-based therapeutic called ImmTAC. ImmTAC-NYE combines a high-affinity TCR extracellular domain for a defined tumour-associated epitope (NY-ESO-1) with a humanised anti-CD3e antibody single chain Fv fragment to activate T cells (pHLA:ImmTAC:CD3). We determined T cell activation by ImmTAC-NYE against a panel of cell lines expressing medium, low and limiting levels of the targeted NY-ESO antigen. Our data demonstrate a positive correlation between NY-ESO-1 abundance and CD8+ CTL activation in tumour cell killing and IFN release. ImmTAC-NYE treated T cells showed greater tumour target cell killing with enhanced T cell infiltration into spheroids as compared to CD8+ T cells expressing a TCR, 1G4, recognising the same antigen. Comparing ImmTAC-NYE variants with different affinities for CD3e, an ImmTAC with intermediate-affinity anti-CD3e showed the best balance between sensitivity and specificity.
Collectively, our 3D spheroid system allowed for a physiologically relevant investigation of the activation of T cell responses to tumour target cell by the ImmTAC-NYE.
Description
This thesis must stay hidden for one year from the award letter, my supervisor from the university of Bristol write down this as the reason for that: "The thesis work was done in collaboration with an industrial partner, Immunocore, as covered by the research agreement 2023 – 3795. The work has used reagents provided by Immunocore that are protected as Immunocore intellectual property. The work is scheduled to be submitted for publication within the next year. To protect Immunocore intellectual property until the manuscript has been accepted, I’m asking for a 1-year deferral of public access to my Ph.D. thesis."
Keywords
Cytotoxic T cells, Melanoma, T cell receptor engagers