Developing novel immunotherapeutic approaches to pancreatic ductal adenocarcinoma (PDAC)

Thesis

Pancreatic ductal adenocarcinoma (PDAC) is a major clinical challenge due to late diagnosis, high metastatic potential, and resistance to conventional therapies. This thesis explores novel immunotherapeutic strategies aimed at improving outcomes in PDAC.

First, a multiparametric flow cytometry panel was developed to comprehensively profile immune alterations in pancreatic tumours and systemic compartments in a mouse model of disease. Using this and other tools, a subset of natural killer (NK) cells expressing markers of tissue retention was identified in mice receiving multimodal therapy; this subset might support anti-tumour immunity indirectly through T cell modulation. Subsequently, another combination regimen was investigated, comprising focal adhesion kinase (FAK) inhibition and T cell immunoreceptor with Ig and ITIM domains (TIGIT) blockade, which demonstrated trends towards enhanced survival and tumour control. Additionally, an in vitro protocol was established to generate cytotoxic NK cells expressing tissue retention markers, which successfully homed to pancreatic tissue in vivo, providing a potential strategy for adoptive NK cell transfer in pre-invasive or early-stage PDAC. Finally, using a different mouse model of disease with slower tumour development revealed progressive accumulation of innate and adaptive lymphocytes during early tumourigenesis. Collectively, these findings provide preliminary support for two conceptual shifts in PDAC immunotherapy that may inform future clinical studies: one towards NK-cell based therapies, and another towards early/preventative interventions.

Authors: Valenzano, G

• DOI: 10.5287/ora-2a6eyvmk0
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: immunotherapy; NK cells; pancreatic cancer; PDAC; immunology
• Subjects: Cancer