Improved dendritic cell therapy for cancer by enhancing in vivo lymph node migration using a novel chemokine-based sorting method

Burgoyne, Paul (2019) Improved dendritic cell therapy for cancer by enhancing in vivo lymph node migration using a novel chemokine-based sorting method. PhD thesis, University of Glasgow.

Abstract

Dendritic cells (DCs) are potent antigen presenting cells and are crucially involved in the induction of the adaptive immune response. Multiple DC subsets exist in the body at rest and during inflammation with unique tissue origins and development. The main function of DCs is the uptake of antigen from the peripheral tissue by endocytosis, and the transfer of this antigen to T cells within the lymph nodes (LNs) to generate an immune response against the antigen. Given the potency of the potential T cell response, DCs are an attractive cell type for therapeutic use in contexts such as cancer. Over 20 years of clinical trials have developed DCs for this purpose: although significant progress has been made, DC clinical trials still show subclinical and variable T cell responses in patients. Numerous strategies have been tested to improve this, including use of specific DC subsets, ex vivo activation and maturation of the cells using cytokines, different antigen loading strategies and different routes of injection. These, however, do not sufficiently take into consideration the migration capability of these injected cells, which severely limits the potential cell function.
CCR7 is the chemokine receptor crucially involved in DC homing to LNs and is a marker of DC maturity, but it has been shown that ex vivo-generated cells do not consistently express this receptor. Using a novel sorting methodology to isolate DCs expressing CCR7, it is possible to improve the maturity and function of the injected cells, as well as in vivo migration. CCR7 expressing cells are more capable of generating mature T cell responses in vitro due to the expression of co-stimulatory molecules such as CD80 and CD86 and the production of T cell-attracting chemokines. The B16F10 mouse melanoma was used to assess the potential improvement in therapeutic DC use following CCR7-sorting. In the subcutaneous model after a single injection, or multiple prophylactic injections, of CCR7- sorted DCs there was significant control of the tumour growth and this resulted in a longer survival duration. This was attributed to the increased T cell response induced by DCs reaching the LN, as more antigen-specific T cells were present in the CCR7-expressing DC-receiving animals and that the T cell phenotype was more mature by surface marker expression. In the metastatic model, however, there was no difference in the overall tumour burden between groups despite having a significantly improved antigen-specific T cell response following injection of the CCR7-sorted DCs. Finally, it was shown that this CCR7-sorting methodology is directly translatable to clinical use using the clinical grade MACSQuant Tyto cell sorter, and that CCR7-sorted human monocyte-derived DCs were also more potent activators of T cells in vitro.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Keywords: dendritic cell, chemokine, CCR7, immunotherapy, cancer therapy.
• Subjects: Q Science > QH Natural history > QH301 Biology; R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer); R Medicine > RM Therapeutics. Pharmacology
• Colleges/Schools: College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Immunology & Infection
• Supervisor's Name: Graham, Professor Gerard and Campbell, Professor John
• Date of Award: 2019
• Depositing User: Mr Paul Burgoyne
• Unique ID: glathesis:2019-39056
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 04 Jan 2019 16:09
• Last Modified: 05 Mar 2020 22:34
• Thesis DOI: 10.5525/gla.thesis.39056
• URI: https://theses.gla.ac.uk/id/eprint/39056