Preclinical models of pancreatic ductal adenocarcinoma and their utility in immunotherapy studies

Abstract

Simple Summary: Immune checkpoint blockade has provided durable clinical responses in a number of human malignancies, but not in patients with pancreatic cancer. Efforts to understand mechanisms of resistance and increase efficacy of immune checkpoint blockade in pancreatic cancer require the use of appropriate preclinical models in the laboratory. Here, we discuss the benefits, caveats, and potentials for improvement of the most commonly used models, including murine-based and patient-derived models. The advent of immunotherapy has transformed the treatment landscape for several human malignancies. Antibodies against immune checkpoints, such as anti-PD-1/PD-L1 and anti-CTLA-4, demonstrate durable clinical benefits in several cancer types. However, checkpoint blockade has failed to elicit effective anti-tumor responses in pancreatic ductal adenocarcinoma (PDAC), which remains one of the most lethal malignancies with a dismal prognosis. As a result, there are significant efforts to identify novel immune-based combination regimens for PDAC, which are typically first tested in preclinical models. Here, we discuss the utility and limitations of syngeneic and geneticallyengineered mouse models that are currently available for testing immunotherapy regimens. We also discuss patient-derived xenograft mouse models, human PDAC organoids, and ex vivo slice cultures of human PDAC tumors that can complement murine models for a more comprehensive approach to predict response and resistance to immunotherapy regimens.