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.

Fig. 1.

Mechanisms by which tumors avoid immune recognition. Mutations in the Ras signaling impair antigen presentation by decreased expression of MHC I and antigen processing molecules. Regulatory T-cells interact with tumor-associated dendritic cells and hamper their immunogenic function by inhibiting the expression of costimulatoiy ligands required for cytotoxic T-cell activity, thus, creating an immunosuppressive environment. Tumor cells also secrete chemokines such as CCL2 and create a physical barrier that prevents immune infiltration. Immunosuppressive immune cells secrete factors such as TGFβ, IL-10, and IL-35 to inhibit CTL activity.

Fig. 2.

Immune checkpoint regulation network in the pancreatic cancer tumor microenvironment. In the tumor microenvironment of pancreatic cancer, the expression of immune checkpoints were regulated by a comprehensive network, including cytokine (red), tumor microenvironment property and key metabolism enzyme (green), key oncogenic, epigenetic, or other signaling pathways (blue), and post-translation modification (separate box) in both cancer cell and immune cells. Other components, such as fibroblasts and macrophages, also contribute to the regulation of immune checkpoints.