Immunotherapy and pancreatic cancer: unique challenges and potential opportunities

Despite decades of research, pancreatic ductal adenocarcinoma (PDAC) continues to have the worst 5-year survival of any malignancy. With 338,000 new cases diagnosed and over 300,000 deaths per year globally there is an urgent unmet need to improve the therapeutic options available. Novel immunotherapies have shown promising results across multiple solid tumours, in a number of cases surpassing chemotherapy as a first-line therapeutic option. However, to date, trials of single-agent immunotherapies in PDAC have been disappointing and PDAC has been labelled as a nonimmunogenic cancer. This lack of response may in part be attributed to PDAC’s unique tumour microenvironment (TME), consisting of a dense fibrotic stroma and a scarcity of tumour infiltrating lymphocytes. However, as our understanding of the PDAC TME evolves, it is becoming apparent that the problem is not simply the immune system failing to recognize the cancer. There is a highly complex interplay between stromal signals, the immune system and tumour cells, at times possibly restraining tumour growth and at others supporting growth and metastasis. Understanding this complexity will enable the development of rational combinations with immunotherapy, priming the TME to offer immunotherapy the best chance of success. This review seeks to describe the unique challenges of the PDAC TME, the potential opportunities it may afford and the trials in progress capitalizing on recent insights in this area.