Exploring novel approaches for developing immunotherapeutic interventions in a mouse model of colorectal cancer

Scott, Jake 2023. Exploring novel approaches for developing immunotherapeutic interventions in a mouse model of colorectal cancer. PhD Thesis, Cardiff University. Item availability restricted.

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Abstract

Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths in the developed world. A substantial body evidence indicates that the degree of T cell infiltration is a key parameter of tumour control and response to treatment. The significant advancement of immune checkpoint blockade therapy has benefited only a small proportion of CRC patients. Most CRC patients are unresponsive to these therapies and new immunotherapeutic approaches are needed to alleviate tumour induced immunosuppression and boost anti-tumour immune responses. FoxP3+ regulatory T cells (Tregs) limit autoimmunity and are increased in frequency in CRC. Whilst there is some evidence that Tregs may limit cancer growth by controlling inflammation in the early stages, there is a body of evidence indicating that they inhibit T cell responses to cancer antigens, helping cancers evade immune attack. In a clinical study carried out by our lab, it was found that treatment of patients with cyclophosphamide (CY) selectively depleted Tregs and correlated with improved T cell (IFN-γ) responses to the cancer associated antigen 5T4. Additionally, vaccination with a modified vaccinia Ankara Virus expressing 5T4 (MVA-5T4; TroVax) also induced robust anti-5T4-IFN-γ T cell responses, correlating with a significant increase in progression-free survival. The project described herein was designed to address unanswered questions emerging from these findings, relating to the mechanism of action of CY and the ability of T cell responses, stimulated by vaccination to directly kill cancer cells. In order to address these questions, it was first necessary to establish a mouse model of CRC. Pre-clinical models of CRC often fail to recapitulate native cellular content, architecture, natural progression and site specificity of the disease. To overcome some of these limitations, this body of work describes the successful colonoscopy-guided implantation of CRC cells into the colonic submucosa of mice. The impact of CY on tumour growth was assessed in these models of CRC. Administration of low-dose metronomic CY depleted Tregs resulting in regression of MC-38 tumours by T cell dependent mechanisms and partial regression of KPNorganoid derived tumours. In parallel, building on the identification of a novel cancer associated antigen in patients with CRC (hDNAJB7), produced a recombinant IX adenoviral (rAd) vector expressing hDNAJB7. The immunogenicity of the rAdhDNAJB7 vector was demonstrated through homologous prime/boost immunisation of mice and a single immunodominant, MHC class I H2-Db restricted epitope was identified. Future experiments will evaluate the anti-tumour effects of vaccination as a monotherapy or in combination with low-dose CY.

Item Type:	Thesis (PhD)
Date Type:	Completion
Status:	Unpublished
Schools:	Medicine
Date of First Compliant Deposit:	10 August 2023
Last Modified:	10 Aug 2023 13:34
URI:	https://orca.cardiff.ac.uk/id/eprint/161565

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