Abstract
Simple SummaryPancreatic cancer is a devastating disease with the worst survival rates of all cancers. Advances in immunotherapy have revolutionized the treatment of cancer, providing cures to patients with a previously lethal disease. Sadly, clinical trials of currently established immunotherapies have not provided significant therapeutic benefits to pancreatic cancer patients. For this reason, alternative treatment approaches that could sensitise the pancreatic tumours to immunotherapy are needed. Therapeutic focused ultrasound is a non-invasive physical modality that can kill cells by raising the temperature, and by disrupting and destroying tissue mechanically. It can also sensitise tumours to the effects of radiotherapy. This review article describes the use of therapeutic focused ultrasound in the treatment of pancreatic cancer. Attention is given to the immunological effects induced by therapeutic focused ultrasound, and how these can be used to sensitise the pancreatic tumours to immunotherapy.Traditional oncological interventions have failed to improve survival for pancreatic cancer patients significantly. Novel treatment modalities able to release cancer-specific antigens, render immunologically “cold” pancreatic tumours “hot” and disrupt or reprogram the pancreatic tumour microenvironment are thus urgently needed. Therapeutic focused ultrasound exerts thermal and mechanical effects on tissue, killing cancer cells and inducing an anti-cancer immune response. The most important advances in therapeutic focused ultrasound use for initiation and augmentation of the cancer immunity cycle against pancreatic cancer are described. We provide a comprehensive review of the use of therapeutic focused ultrasound for the treatment of pancreatic cancer patients and describe recent studies that have shown an ultrasound-induced anti-cancer immune response in several tumour models. Published studies that have investigated the immunological effects of therapeutic focused ultrasound in pancreatic cancer are described. This article shows that therapeutic focused ultrasound has been deemed to be a safe technique for treating pancreatic cancer patients, providing pain relief and improving survival rates in pancreatic cancer patients. Promotion of an immune response in the clinic and sensitisation of tumours to the effects of immunotherapy in preclinical models of pancreatic cancer is shown, making it a promising candidate for use in the clinic.
Highlights
Tumours in the pancreas begin as pancreatic intraepithelial neoplasias (PanIN), and subsequent mutations cause them to progress to tumours [1,2,3]
The majority of the resulting primary pancreatic tumours are pancreatic ductal adenocarcinomas located in the head of the pancreas, and metastasis can occur before their enlargement and detection [11,12]
The stroma contains pancreatic stellate cells (PSC) which regulate the tumoural microenvironment [28,29], cytokine and chemokine-responsive tumour associated macrophages (TAM) which contribute to desmoplasia and immunosuppression [30,31], Tregulatory cells, myeloid-derived suppressor cells (MDSC) which build crosstalk with TAM and suppress the effector T
Summary
The stroma contains pancreatic stellate cells (PSC) which regulate the tumoural microenvironment [28,29], cytokine and chemokine-responsive tumour associated macrophages (TAM) which contribute to desmoplasia and immunosuppression [30,31], Tregulatory cells, myeloid-derived suppressor cells (MDSC) which build crosstalk with TAM and suppress the effector T cells [32,33] and cancer-associated fibroblasts (CAF) [34]. The latter are differentiated from resident fibroblasts, activated PSCs, adipocytes and tumour-infiltrating mesenchymal stem cells [35], and can create an immunosuppressive microenvironment [36,37,38,39,40,41,42,43]. The need for a more targeted approach against the pancreatic tumour microenvironment has become clear and recently, improved response rates in patients with high levels of hyaluronic acid in their tumours, have been obtained from a phase I/II study (NCT01839487) which combined a high molecular weight hyaluronan inhibitor PEGPH20 with gemcitabine [47]
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