Immunotherapy of pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is predicted to become the second most common cause of cancer-related death in the United States by 2030. So far surgery remains the only curative option for pancreatic cancer, but fewer than 20% of patients have surgically resectable disease. Furthermore, pancreatic cancer exhibits a remarkable resistance to established therapeutic options, including chemotherapy, radiotherapy, and targeted therapy, because pancreatic cancer exhibits numerous mechanisms of resistance like genetic and epigenetic alterations and a complex and dense tumor microenvironment. The tumor microenvironment is populated with different types of immune cells that play a critical role in therapy resistance, tumor progression, and carcinogenesis. Cancer immunotherapy has now been recognized as the fourth pillar of cancer care and a number of preclinical and clinical studies have been conducted for pancreatic cancer. Targeting and modulating the tumor immune microenvironment could not only switch the immune system toward anti-cancer, but also may improve sensitivity toward established chemotherapy. In this review, we discuss both preclinical and clinical studies on pancreatic cancer immunotherapy with natural killer cells, dendritic cells, and chimeric antigen receptor T cells. Furthermore, we summarize strategies for reprogramming the tumor immune microenvironment by targeting macrophages and stromal cell factors in pancreatic cancer. The development of systemic therapies is essential for improving the outcomes of pancreatic cancer patients, and cancer immunotherapy would improve effectiveness of other established therapeutic options, which might together improve the prognosis of pancreatic tumors.