Immune checkpoint blockade in pancreatic cancer: Trudging through the immune desert

Abstract

Pancreatic cancer (PC) has exceptionally high mortality due to ineffective treatment strategies. Immunotherapy, which mobilizes the immune system to fight against cancer, has been proven successful in multiple cancers; however, its application in PC has met with limited success. In this review, we articulated that the pancreatic tumor microenvironment is immuno-suppressive with extensive infiltration by M2-macrophages and myeloid-derived suppressive cells but low numbers of cytotoxic T-cells. In addition, low mutational load and poor antigen processing, presentation, and recognition contribute to the limited response to immunotherapy in PC. Immune checkpoints, the critical targets for immunotherapy, have high expression in PC and stromal cells, regulated by tumor microenvironmental milieu (cytokine and metabolites) and cell-intrinsic mechanisms (epigenetic regulation, oncogenic signaling, and post-translational modifications). Combining immunotherapy with modulators of the tumor microenvironment may facilitate the development of novel therapeutic regimens to manage PC.

Keywords: Cancer-associated fibroblast; Combination therapy; Cytokine; Immune checkpoint; Immunotherapy; Pancreatic cancer; Regulation network; Tumor microenvironment.