Immune Evasion in Pancreatic Cancer: From Mechanisms to Therapy

Abstract

Pancreatic ductal adenocarcinoma (PDA), the most frequent type of pancreatic cancer, remains one of the most challenging problems for the biomedical and clinical fields, with abysmal survival rates and poor therapy efficiency. Desmoplasia, which is abundant in PDA, can be blamed for much of the mechanisms behind poor drug performance, as it is the main source of the cytokines and chemokines that orchestrate rapid and silent tumor progression to allow tumor cells to be isolated into an extensive fibrotic reaction, which results in inefficient drug delivery. However, since immunotherapy was proclaimed as the breakthrough of the year in 2013, the focus on the stroma of pancreatic cancer has interestingly moved from activated fibroblasts to the immune compartment, trying to understand the immunosuppressive factors that play a part in the strong immune evasion that characterizes PDA. The PDA microenvironment is highly immunosuppressive and is basically composed of T regulatory cells (Tregs), tumor-associated macrophages (TAMs), and myeloid-derived suppressive cells (MDSCs), which block CD8+ T-cell duties in tumor recognition and clearance. Interestingly, preclinical data have highlighted the importance of this immune evasion as the source of resistance to single checkpoint immunotherapies and cancer vaccines and point at pathways that inhibit the immune attack as a key to solve the therapy puzzle. Here, we will discuss the molecular mechanisms involved in PDA immune escape as well as the state of the art of the PDA immunotherapy.

Bioinformatics profiling utilized a nine immune‐related long noncoding RNA signature as a prognostic target for pancreatic cancer

“…7,8 Meanwhile, the immune microenvironment of pancreatic cancer is extremely suppressive and dysregulated on the basis of myeloid-derived suppressive cells, immunosuppressive macrophages, and T regulatory cells (Tregs). 5 Therefore, it is worth considering how immune-related factors are identified.…”

Targeting tumor-intrinsic metabolic node sensitizes pancreatic cancer to anti-PD1 therapy

“…Pancreatic ductal adenocarcinoma (PDAC) is considered to be a highly immunosuppressive and heterogeneous neoplasm (6,74). Despite improved knowledge regarding the genetic background of the tumor and better understanding of the tumor microenvironment, immune checkpoint inhibitor therapies (using CTLA-4, PD-1, PD-L1), that have shown effect in other solid tumors, have not been very successful in PDAC.…”

“…Compounding this, the pancreatic tumor is largely immune evasive. This makes these tumors resistant to immune checkpoint inhibitor therapies (with anti-PD1, anti-PDL1 and anti-CTLA4 therapy) that have shown remarkable benefit in other tumors (5,6).…”

Targeting dual signaling pathways in concert with immune checkpoints for the treatment of pancreatic cancer

“…However, single agent immunotherapy treatments have generally not been successful in pancreatic cancer 20-22 . This lack of response may in part be attributed to the presence of dense desmoplastic stroma, the relatively low level of quality neo-epitopes, and the activation of multiple immune suppressive features of the tumor microenvironment 21-25 . Understanding the complex interplay between tumor cell and stromal compartment and agents that target these components have been utilized in combination with immune modulating treatments and have shown promising results 26, 27 .…”