Nattress, Callum Baird;
(2024)
Single-Cell Signalling Analysis of γδ T Cell Biotherapeutics for the Treatment of Colorectal Cancer.
Doctoral thesis (Ph.D), UCL (University College London).
Preview |
Text
Nattress_10198936_thesis.pdf Download (90MB) | Preview |
Abstract
Colorectal cancer (CRC) is a devastating disease that is responsible for the deaths of >900,000 people worldwide annually, with immunotherapies struggling against the immunosuppressive CRC tumour microenvironment (TME). Tumour infiltrating γδ T cells confer a prognostic benefit to CRC patients and can kill cancer cells via antibodyindependent cytotoxicity (AIC) and antibody-dependent cellular cytotoxicity (ADCC). Therefore, γδ T cells are under intense investigation as anti-cancer biotherapeutics, however, the relative contribution of AIC and ADCC performed by these anti-tumour cellular therapies is unknown. Furthermore, how γδ T cells communicate with cancer in a bidirectional and reciprocal manner across multiple γδ T cell donors and cancer patients is poorly understood. Here, I describe a single-cell phenoscape of >1,000 γδ T cell and CRC patient-derived organoid (PDO) cultures, spanning inter-donor heterogeneity (IDH), inter-tumour heterogeneity (ITH), and multimodal cytotoxicity. Singlecell analysis of post-translational modification (PTM) signalling, cell-cycle, apoptosis, and T cell immunophenotypes revealed that while unmodified γδ T cells have limited anti-tumour activity, IL-15Rα-IL-15 fusion protein (stIL15)-engineered γδ T cells can kill PDOs via AIC without exogenous cytokine support. However, when stIL15 γδ T cells only kill via AIC, cancer cells can re-wire γδ T cell PTM signalling networks in a patient-specific manner to suppress anti-cancer cytotoxicity. stIL15-γδ T cells can overcome this cancer cell immunomodulation by also engaging B7-H3-targeted ADCC. Combined AIC and ADCC rescues γδ T cell PTM signalling flux and increases anticancer cytotoxicity beyond chemotherapy against both microsatellite instable (MSI) and stable (MSS) CRC. These results demonstrate that multimodal γδ T cell killing mechanisms can overcome patient-specific immunomodulation of anti-solid tumour cellular therapies.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Single-Cell Signalling Analysis of γδ T Cell Biotherapeutics for the Treatment of Colorectal Cancer |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2024. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10198936 |
Archive Staff Only
 |
View Item |
