Sonodynamic therapy complements PD-L1 immune checkpoint inhibition in a murine model of pancreatic cancer

• Published in: Cancer letters Vol. 517; pp. 88 - 95
• Main Authors: Nesbitt, Heather, Logan, Keiran, Thomas, Keith, Callan, Bridgeen, Gao, Jinhui, McKaig, Thomas, Taylor, Mark, Love, Mark, Stride, Eleanor, McHale, Anthony P., Callan, John F.
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier B.V 01.10.2021; Elsevier Limited
• Subjects: Adaptive immunity; Animal models; Animals; Antibodies; Antibodies, Monoclonal - immunology; Apoptosis; Apoptosis - immunology; Aqueous solutions; B7-H1 Antigen - immunology; Cancer immunotherapy; Cancer therapies; Cavitation; CD4 antigen; CD4-Positive T-Lymphocytes - immunology; CD8 antigen; CD8-Positive T-Lymphocytes - immunology; Cell death; Colorectal carcinoma; Disease Models, Animal; Glycerol; Immune checkpoint inhibitor; Immune checkpoint inhibitors; Immune Checkpoint Inhibitors - immunology; Immune response; Lymphocytes T; Mice; Mice, Inbred C57BL; Monoclonal antibodies; Pancreatic cancer; Pancreatic Neoplasms - immunology; Pancreatic Neoplasms - therapy; PD-1 protein; PD-L1; PD-L1 protein; Polyethylene glycol; Radiation therapy; Reactive oxygen species; Reactive Oxygen Species - immunology; Sonodynamic therapy; Tumors; Ultrasonic imaging; United Kingdom > UK; United States > US; Japan; PD-L1; Immune checkpoint inhibitor; Sonodynamic therapy; Pancreatic cancer
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2021.06.003

The emergence of immune checkpoint inhibitors (ICI's) in the past decade has proven transformative in the area of immuno-oncology. The PD-1/PD-L1 axis has been particularly well studied and monoclonal antibodies developed to block either the receptor (anti PD-1) or its associated ligand (anti PD-L1) can generate potent anti-tumour immunity in certain tumour models. However, many “immune cold” tumours remain unresponsive to ICI's and strategies to stimulate the adaptive immune system and make these tumours more susceptible to ICI treatment are currently under investigation. Sonodynamic therapy (SDT) is a targeted anti-cancer treatment that uses ultrasound to activate a sensitiser with the resulting generation of reactive oxygen species (ROS) causing direct cell death by apoptosis and necrosis. SDT has also been shown to stimulate the adaptive immune system in a pre-clinical model of colorectal cancer. In this manuscript, we investigate the ability of microbubble mediated SDT to control tumour growth in a bilateral tumour mouse model of pancreatic cancer by treating the target tumour with SDT and observing the effects at the off-target untreated tumour. The results demonstrated a significant 287% decrease in tumour volume when compared to untreated animals 11 days following the initial treatment with SDT, which reduced further to 369% when SDT was combined with anti-PD-L1 ICI treatment. Analysis of residual tumour tissues remaining after treatment revealed increased levels of infiltrating CD4+ and CD8+ T-lymphocytes (respectively 4.65 and 3.16-fold more) in the off-target tumours of animals where the target tumour was treated with SDT and anti-PD-L1, when compared to untreated tumours. These results suggest that SDT treatment elicits an adaptive immune response that is potentiated by the anti-PD-L1 ICI in this particular model of pancreatic cancer. •SDT treatment of pancreatic tumours in mice causes significant tumour growth regression in off-target untreated tumours.•SDT compliments immune checkpoint inhibitor treatment further enhancing tumour regression.•Increased CD4+ and CD8+ T-lymphocytes were observed in harvested tumours suggesting SDT stimulates a host immune response.