Abstract
Periampullary cancers (PACs) are characterized by tumor-infiltrating lymphocytes (TILs), severe fibrosis, and epithelial to mesenchymal transition (EMT). The immune checkpoint marker programmed death-1 (PD-1) and its ligands 1 and 2 have gained popularity in cancers with TILs. Evidence suggests a strong relationship between immune checkpoint markers and EMT in cancers. Here, we evaluated the expression and prognostic significance of immune checkpoint and EMT markers in PAC using an automated image analyzer. Formalin-fixed, paraffin-embedded surgically excised PAC tissues from laboratory archives (1998–2014) were evaluated by immunohistochemical staining for PD-1, PD-L1, and PD-L2 in a tissue microarray. In total, 115 PAC patients (70 males and 45 females) with an average age of 63 years were analyzed. Location, gross type, size, radial resection margin, N-M stage, lymphatic invasion, vascular invasion, perineural invasion, histologically well-differentiated severe inflammation, and high PD-L1 expression were significantly associated with recurrence. Higher PD-L1 expression, but not PD-1 and PD-L2, was significantly related to better overall survival (OS) and disease-free survival (DFS). PD-L1 and PD-L2 were significantly related to EMT markers. Aside from other clinicopathologic parameters, high PD-L1 expression was significantly related to better OS and DFS of PAC patients. Moreover, immune checkpoint markers were significantly associated with EMT markers. Therefore, PD-L1 expression can be a good prognostic marker to guide future immune target-based therapies in PAC patients.
Highlights
Periampullary cancers (PACs), including pancreatic ductal adenocarcinoma, ampulla of Vater (AOV), and common bile duct (CBD) cancers, are highly lethal malignancies and predicted to be the second most common cause of cancer-related death after lung cancer by2030 [1,2]
The tumor microenvironment is characterized by profound desmoplasia, epithelial-mesenchymal transition (EMT), cancer stem cells, and immunosuppressive cell infiltrates, which seem to contribute to chemotherapeutic resistance [5,6]
The immune checkpoint marker programmed death-1 (PD-1) and its ligands programmed death ligand-1 (PD-L1) and programmed death ligand-2 (PD-L2) have attracted interest in the field of cancer immunology owing to conflicting prognostic significance [7]
Summary
Periampullary cancers (PACs), including pancreatic ductal adenocarcinoma, ampulla of Vater (AOV), and common bile duct (CBD) cancers, are highly lethal malignancies and predicted to be the second most common cause of cancer-related death after lung cancer by. The immune checkpoint marker programmed death-1 (PD-1) and its ligands programmed death ligand-1 (PD-L1) and programmed death ligand-2 (PD-L2) have attracted interest in the field of cancer immunology owing to conflicting prognostic significance [7]. The blockade of this pathway using specific inhibitors such as pembrolizumab and nivolumab could enhance the cytotoxicity of T cells in the tumor environment and substantially increase the long-term survival in different cancers [7,8,9]. We scrutinized the correlation of these markers with clinicopathological features and determined their prognostic significance
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