Harnessing epigenetic regulation to improve cancer therapy

Thesis

Melanoma antigen gene (MAGE)-type antigens are attractive targets for cancer vaccines due to their overexpression in a wide range of tumour types and restriction in normal tissues. Previous studies showed that combining vaccines targeting the murine MAGE equivalent P1A with checkpoint inhibitors (CPIs) could effectively control tumours with high P1A expression. Our work extends this approach in tumours with low or no P1A expression and without using CPIs. These conditions better reflect the challenges seen in human cancers. As MAGE-type genes are regulated through epigenetic mechanisms, using epigenetic modulators could be a promising approach to increase MAGE-type antigen expression and enhance vaccine efficacy. In this project, we assess the combination of DNA methyltransferase inhibitors (DNMTi) for their potential to increase the murine MAGE-type antigen P1A expression. We show that DNMTis upregulate P1A expression at the transcriptional and protein levels, and increase and enhance MHC-class I presentation in vitro. DNMTi pre-sensitised tumour cells were implanted into C57BL/6 mice, and viral vector vaccination encoding the P1A-antigen delayed tumour growth. However, combination treatment of DNMTi with P1A-antigen based viral vector vaccines was unable to potentiate the vaccine induced anti-tumour effect in B16F10 tumour bearing mice, and even decreased the vaccine induced response in the OVA-model. Further investigation of DNMTi effect on primary T cells ex vivo resulted in decreased proliferation and effector cytokine secretion. P1A-specific CD8+ T cells did not recognise DNMTi or IFNy pre-treated P1A-expressing tumours in a co-culture setting, raising the question whether P1A is indeed presented on MHC-class I. Assessing the toxicity of epigenetic drug treatment in vivo in tumour-free mice revealed a transient and short-term depletion of lymphocytes. Vaccination with viral vectors ChAdOx1/MVA encoding P1A induced a potent P1A-specific CD8+ T-cell response, but surprisingly, mice pre-treated with DNMTi had a drastic decrease of P1A-specific CD8+ T cells. These findings suggest that DNMTi treatment weakens the vaccine response by reducing CD8+ T cell activation and proliferation. Additionally, the self-antigen nature of P1A most likely triggers immune tolerance mechanisms, further limiting the development of a robust therapeutic response.

Authors: Wicki, A

• DOI: 10.5287/ora-vm9roob50
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: immunotherapy; epigenetics; cancer vaccines
• Subjects: Cancer--Immunotherapy