Pancreatic Ductal Adenocarcinoma (PDAC) has the worst 5-year survival of all cancer types. Treatment options for these patients are limited and consist mainly of chemotherapy. However, the unique tumour microenvironment with its dense, fibrotic shield causes resistance to current and novel therapies. Tackling this stromal shield is therefore deemed crucial for making progress in PDAC treatment. We investigated in this thesis the potential of Natural Killer (NK) cells to address this high medical need. Firstly, our systematic review revealed strong evidence of their importance in PDAC and how the tumour renders them into a suppressed and less functional state. Based on this information, we sought to stimulate NK cells in such way that they attack both tumour and surrounding stroma. We show that, upon stimulation with IL-15, NK cells are capable of killing both pancreatic cancer and stellate cells, the drivers of the stromal reaction, in a contact-dependant manner. Increased expression of NKG2D and TIM-3 receptors was partially responsible for this enhanced killing. Furthermore, in our search to potentiate IL-15 stimulation, we combined this with an immune priming CD40 agonist and demonstrated profound anti-tumour effects and prolonged survival in PDAC mouse models. Increased intra-tumoral cytotoxic T cells, NK cells and reduced T regulatory cells combined with increased cross-presenting dendritic cells in the tumour draining lymph nodes are the main effectors of the observed anti-tumour effects. Summarised, our data provide a strong rationale for NK cell-driven cancer immunotherapy where immune stimulation is combined with immune priming. Initiation of an early-phase clinical trials with this novel combination immunotherapy for PDAC patients is warranted.
BELG J MED ONCOL 2021;15(3):128-31