Combination immunotherapy for pancreatic cancer: challenges and future considerations

Introduction Immune checkpoint inhibitors (ICI) have not yielded significant efficacy in pancreatic ductal adenocarcinoma (PDA), despite the role of the innate and adaptive immune systems on progression and survival. However, recently identified pathways have identified new targets and generated promising clinical investigations into promoting an effective immune-mediated antitumor response in PDA. Areas covered We review biological mechanisms associated with immunotherapy resistance and outline strategies for therapeutic combinations with established and novel therapies in PDA. Expert opinion Pancreatic cancers rarely benefit from treatment with ICI due to an immunosuppressive tumor microenvironment (TME). New understandings of factors associated with the suppressive TME include low- and poor-quality neoantigens, constrained effector T cells infiltration, and the presence of a dense, suppressive myeloid cell population. These findings have been translated into new clinical investigations evaluating novel therapies in combination with ICI and/or standard systemic chemotherapy and radiotherapy. The epithelial, immune, and stromal compartments are intricately related in PDA, and the framework for successful targeting of this disease requires a comprehensive and personalized approach.

Automated summary

Despite the role of immune systems on progression and survival, immune checkpoint inhibitors (ICI) have not been effective in treating pancreatic ductal adenocarcinoma (PDA). However, recent pathways have identified new targets and generated promising clinical investigations for promoting an effective immune response in PDA.