PRMT5 inhibition as a strategy to induce immunogenicity in pancreatic ductal adenocarcinoma

Thesis

Pancreatic ductal adenocarcinoma (PDAC) is a disease with high mortality rates where conventional chemotherapeutics have shown limited efficacy. Mutation of key driver genes and the presence of a highly acidic tumour microenvironment generate a permanent state of low antigenicity and sustained immunosuppression that is at the core of PDAC therapeutic failure. Here is shown that PRMT5 inhibition is a promising pharmacological approach to enhance PDAC immunogenicity and improve its microenvironmental conditions. Results reveal that PDAC cells under PRMT5 inhibition are capable to slightly activate T and NK cells in tumour sites and induce the expression and translation of immunogenic lncRNA-derived peptides that are capable to reduce tumour growth in vivo. PRMT5 inhibition also alters pH dynamics in a bicarbonate-dependent fashion by promoting the skipping of exon 25 of the sodium/bicarbonate co-transporter SLC4A7. These findings highlight the potential of PRMT5 inhibition as a dual immunosensitizing strategy for PDAC treatment, which can provide a platform for future studies involving combinatorial treatments or deeper mechanistic understanding.

Authors: Reyna Jeldes, D

• DOI: 10.5287/ora-obavmvz40
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: PRMT5 inhibitor; SLC4A7; lncRNA-derived peptides; PDAC