Emerging Role of Immune Checkpoint Blockade in Pancreatic Cancer

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.

Low CD8⁺ T Cell Infiltration and High PD-L1 Expression Are Associated with CD44⁺/CD133⁺ Cancer Stem Cells and Predict an Unfavorable Prognosis in Pancreatic Cancer

“…Several studies focused on PC have achieved similar results showing that PD-L1 expression in tumor tissues is associated with tumor growth, TNM stage, and patients' survival [8,51]. In our study, although PD-L1 expression was not correlated with patients' survival, it was associated with PC recurrence.…”

“…Critical obstacles to immunotherapy in PC can be explained by the low immunogenicity and immunosuppressive TME of these tumors [27,55]. The TME mainly consists of stromal cells including fibroblasts, immune and inflammatory cells, the blood and lymphatic vascular networks, and extracellular matrix [56].…”

“…Most treatment failures are due to local recurrence, local and/or distant micrometastases, or both and occur within 2 years after surgery [6,7]. Despite the fact that systemic chemotherapy is the mainstay of treatment in patients with unresectable PC, the treatment and survival outcomes remain poor [8,9]. Therefore, developing novel therapeutic strategies for this fatal disease is urgently needed.…”

“…PD-L1 is the main ligand for PD-1, which is crucial for suppressing T cell proliferation, migration, and secretion of cytotoxic mediators, and thus blocks the antitumor immune responses by binding to PD-1 [25]. Several studies have evaluated the expression of PD-L1 on the surface of tumor cells, and suggested that PD-L1 expression can either relate to poor prognosis, better prognosis or show no association with prognosis for various malignancies including PC [26][27][28]. An early preclinical study has demonstrated that PD-L1 blockade promoted CD8 + T cell infiltration into the tumor and induced a substantial antitumor effect in a mouse tumor transplant model [29].…”

A Combination of Radiotherapy, Hyperthermia, and Immunotherapy Inhibits Pancreatic Tumor Growth and Prolongs the Survival of Mice

“…Though RT and hyperthermia exert pro-immune effects on the TME, those responses can likely be further directly enhanced with immune stimulation using immunotherapy agents. Immunotherapy, in the form of check-point inhibitors targeting CTLA4 and PD1, has shown remarkable responses in select malignancies, but has not shown clinical efficacy for pancreatic cancer [20][21][22][23][24]. We therefore examined a different class of immunotherapy, focusing on OX40 activation via agonistic antibody [25,26].…”