Abstract
Immune checkpoint blockade (ICB) with programmed cell death protein-1(PD-1)/programmed death ligand -1(PD-L1) antibodies has revolutionized the management of several cancers, especially non-small cell lung cancer, melanoma, urothelial, and renal cancer. Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancers associated with high morbidity and mortality. Based on available data, it’s obvious that ICB has limited success in PDACs, which can be explained by the low immunogenicity and immunosuppressive tumor microenvironment of these tumors. In this review article, we focus on PD-L1 expression and microsatellite instability (MSI) in PDAC, and their roles as prognostic and predictive markers. We also discuss data supporting combination therapies to augment cancer immunity cycle. Combining anti-PD-1/PD-L1 agents with other modalities such as vaccines, chemotherapy, and radiation could potentially overcome resistance patterns and increase immune responsiveness in PDAC.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with a dismal five year overall survival(OS) rate of 8.5%, making it the third leading cause of cancer-related death, with an estimated 55,400 new cases and 44,330 deaths in the United States in 2018 [1]
PDAC poses several treatment challenges, including late presentation and a unique tumor microenvironment characterized by dense desmoplasia and intense infiltrations of immunosuppressive cells [3,4] contributing to chemotherapy resistance
Despite recent advances in combination chemotherapy regimens, PDAC remains a deadly malignancy with dismal outcomes
Summary
Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with a dismal five year overall survival(OS) rate of 8.5%, making it the third leading cause of cancer-related death, with an estimated 55,400 new cases and 44,330 deaths in the United States in 2018 [1]. By interaction with a host immune system, the malignant cells may determine its fitness for survival and growth, thereby aiding the malignant cell to evade the tumor suppressor function of the immune system, that is, if the immune response fails to eliminate the tumor. Immune checkpoint regulators, such as programmed cell death-1 and cytotoxic T lymphocyte antigen-4 (CTLA-4), belong to a class of co-inhibitory receptors present mainly on T cells. Direct and indirect utilization of these co-inhibitory pathways by tumors results in their ability to evade an immune attack This mechanism, termed adaptive immune resistance, facilitates tumor growth and propagation. Immune-checkpoint antibodies directed against PD-1 and PD-L1 restore antitumoral immunity by augmentation of an endogenous immune response [12]
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