Engineering an ICD stimulated dendritic cell derived exosome-mimetic vaccine against cancer antigens

Abstract

Over the last decade, cancer immunotherapy in the form of immune checkpoint inhibitor (ICI) therapy has provided an effective treatment strategy for several cancer types that are unresponsive to other forms of treatment. However, a large subset of solid tumours, designated as being “cold” in nature, cannot respond to ICI therapy due to limited T-cell infiltration within the tumour following the suppression of antigen-presenting cells (APCs) inside the tumour microenvironment. Dendritic cell (DC) vaccines, which focus on the ex vivo stimulation, and subsequent patient reinfusion, of tumour antigen cross-presenting DCs, provide a method to combat this immunosuppression. However, despite the potential possessed by this approach, the reliance on transient live DC populations poses both logistical and financial complications that may block their widespread clinical application. This method could be improved by using DC-derived exosome like vesicles (DC ELVs), which can be formed by extruding mature tumour antigen-presenting DCs. Such DC ELVs possess the entire complement of peptide-MHC molecules and T-cell co-receptors present on the surface of the parent dendritic cells, allowing them to bring about a cell-mediated tumour immune response while maintaining a much greater level of stability. While such cell membrane-derived vesicles have been studied in several ways in the context of cancer therapy (e.g. drug delivery and tumour targeting), their use in a vaccine setting has been limited up to this point. This project’s central aim is to produce DC ELVs from DCs that have been pulsed with tumour cells undergoing ICD to provide a nanoscale acellular cancer vaccine. We first demonstrated the induction of the ICD phenotype within the CT26 cell line following mitoxantrone treatment. Following this, we produced an ICD pulsed DC ELV formulation, which we showed to conserve the surface-marker integrity of the parent cells and display stimulatory activity within primary-DC populations.

Thesis is embargoed until 31 December 2026.

Date of Award	Dec 2023
Original language	English
Awarding Institution	Queen's University Belfast
Sponsors	Northern Ireland Department for the Economy
Supervisor	Jonathan Coulter (Supervisor) & Wafa Al-Jamal (Supervisor)