Therapeutic targeting of γδ t cells and positron emission tomography imaging of immune cell activation
File(s)
Author(s)
Amgheib, Ala
Type
Thesis
Abstract
Cancer immunotherapy has revolutionised the way malignancies are treated but its success remains limited to a small fraction of patients1,2. Therefore, there is an increasing demand for improved treatment and mentoring methods. This study investigates the potential of γδ T cells in cancer treatment and explores the application of positron emission tomography (PET) imaging for monitoring immune cell activation, facilitating treatment evaluation.
Cancer-targeted delivery of aminobisphosphonates (N-BisP) was proposed to improve the therapeutic potential of γδ T cells3. An attempt to develop a compound consisting of N-BisP conjugated to prostate-specific membrane antigen (PSMA) peptide was made but did not yield the anticipated product. Nevertheless, the ability of N-BisP components of the PSMA-N-BisP compound to promote γδ T cell expansion was assessed. AIE-BisP demonstrated an increase in the yield of γδ T cells by 44.75 ± 3.23 %. Thus, PSMA-AIE-BisP compound may enhance γδ T cell expansion at the tumour site. This thesis further explored the potential to improve the susceptibility of prostate cancer (PCa) cells to γδ T cell-mediated cytotoxicity by increasing Butyrophilin 3A1 (BTN3A1) expression via Bortezomib (BTZ). Although BTZ resulted in a 1.92-fold upregulation of BTN3A1 protein in PCa cell line, 22RV1, it did not improve PCa sensitivity to γδ T cells. To detect immune activation, two PET probes, [18F]TTCO-IL-2 and [18F]NT-TTCO-IL-2, were developed but both exhibited poor sensitivity to CD25 upregulation. Studies with FITC-TTCO-IL-2 and FITC-IL-2 indicate that the addition of TTCO-PEG4 moiety to lysine residues in IL-2 hinders its sensitivity to CD25. However, fluorescent NT-TTCO-IL-2 probe demonstrated sensitivity to CD25 upregulation, insinuating that site-specific conjugation of TTCO-PEG4 to IL-2 could potentially yield a PET probe capable of detecting activated immune cells.
Overall, these findings provide insights into approaches to improving the efficacy of γδ T cells and a method for capturing the pharmacodynamics of immune cells.
Cancer-targeted delivery of aminobisphosphonates (N-BisP) was proposed to improve the therapeutic potential of γδ T cells3. An attempt to develop a compound consisting of N-BisP conjugated to prostate-specific membrane antigen (PSMA) peptide was made but did not yield the anticipated product. Nevertheless, the ability of N-BisP components of the PSMA-N-BisP compound to promote γδ T cell expansion was assessed. AIE-BisP demonstrated an increase in the yield of γδ T cells by 44.75 ± 3.23 %. Thus, PSMA-AIE-BisP compound may enhance γδ T cell expansion at the tumour site. This thesis further explored the potential to improve the susceptibility of prostate cancer (PCa) cells to γδ T cell-mediated cytotoxicity by increasing Butyrophilin 3A1 (BTN3A1) expression via Bortezomib (BTZ). Although BTZ resulted in a 1.92-fold upregulation of BTN3A1 protein in PCa cell line, 22RV1, it did not improve PCa sensitivity to γδ T cells. To detect immune activation, two PET probes, [18F]TTCO-IL-2 and [18F]NT-TTCO-IL-2, were developed but both exhibited poor sensitivity to CD25 upregulation. Studies with FITC-TTCO-IL-2 and FITC-IL-2 indicate that the addition of TTCO-PEG4 moiety to lysine residues in IL-2 hinders its sensitivity to CD25. However, fluorescent NT-TTCO-IL-2 probe demonstrated sensitivity to CD25 upregulation, insinuating that site-specific conjugation of TTCO-PEG4 to IL-2 could potentially yield a PET probe capable of detecting activated immune cells.
Overall, these findings provide insights into approaches to improving the efficacy of γδ T cells and a method for capturing the pharmacodynamics of immune cells.
Version
Open Access
Date Issued
2023-11-05
Date Awarded
01/05/2024
Advisor
Aboagye, Eric
Ghaem-Maghami, Sadaf
Publisher Department
Department of Surgery & Cancer
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)