Pancreatic Ductal Adenocarcinoma and Immune Checkpoint Inhibitors: The Gray Curtain of Immunotherapy and Spikes of Lights

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a dismal disease with a poor 5-year overall survival rate (~10%). The revolution of immunotherapy in clinical oncology has not substantially changed clinical outcome for patients with PDAC. Despite outstanding efforts, neither immune checkpoint inhibitors (ICIs) alone, nor in combination with chemotherapy or targeted therapies have shown encouraging results. This failure mirrors the lack of knowledge about the real key players of immune system senescence and the complexity of the tumor microenvironment in PDAC. However, some hope can be derived from PARP-inhibitor combinations, vaccines, and CAR-T-cells therapy. In this review, we comprehensively summarize the latest updates about the use of ICIs in PDAC, focusing on clinical evidence and ongoing studies highlighting explanations for the failure of immunotherapy and possible solutions.

Metastatic Pancreatic Cancer: Where Are We?

“…Research is also underway to determine the extent of cancer risk associated with PALB2 (partner and localizer of BRCA2), which occurs in 3%–4% of familial pancreatic cancer cases [ 14 , 34 ]. Promising preclinical studies are currently underway, based on CAR-T-Cell therapy, which is based on the collection of T cells genetically modified to express an antigen-binding domain capable of recognizing and attacking cancer cells [ 35 , 36 ]. Another treatment strategy is represented by vaccines, emerging as innovative immunotherapies, also evaluated in combination with chemotherapy.…”

“…Another treatment strategy is represented by vaccines, emerging as innovative immunotherapies, also evaluated in combination with chemotherapy. One of the best-investigated vaccine strategies is granulocyte-macrophage colony-stimulating factor (GMCSF)-allogeneic pancreatic tumor cells (GVAX) [ 35 , 37 ].…”

Stromal and tumor immune microenvironment reprogramming through multifunctional cisplatin-based liposomes boosts the efficacy of anti-PD-1 immunotherapy in pancreatic cancer

“…6 Nevertheless, pancreatic cancer patients had a poor response to immunotherapy. 7–9 Increasing evidence shows that the dense stromal barrier in pancreatic cancer tissues blocks intratumoral delivery and distribution of therapeutic drugs. 10 Stromal physical and immune suppressive biological barriers in the tumor microenvironment further limit the number and function of cytotoxic CD8 + T cells and prevent infiltration of cytotoxic T cells in the tumor.…”

Current and future immunotherapeutic approaches in pancreatic cancer treatment

“…This persistent tumor primarily escapes immune detection through various means, including the secretion of immunosuppressive factors like transforming growth factor-beta (TGF-β), the creation of an immunosuppressive environment lacking T lymphocytes, and the expression of immune checkpoints such as programmed death-ligand 1 (PD-L1) and PD-L2 [ 4 , 34 ]. Furthermore, research is being conducted on ICB to activate T-cell function in pancreatic cancer [ 35 – 37 ]. The pancreatic cancer microenvironment is characterized by extensive desmoplasia, a scarcity of effector T lymphocytes, and an immunophenotype dominated by T helper 2 (TH2) cells, all of which facilitate the evasion of cancer cells from immune surveillance [ 38 – 40 ].…”