Abstract
Pancreatic ductal adenocarcinoma (PDAC) being characterized by a pronounced stromal compartment is commonly diagnosed at an advanced stage limiting curative treatment options. Although therapeutical targeting of immune checkpoint regulators like programmed death 1 ligand 1 (PD-L1) represent a promising approach that substantially improved survival of several highly aggressive malignancies, convincing indicators for response prediction are still lacking for PDAC which might be attributed to the insufficient characterization of PD-L1 status. Therefore, we investigated PD-L1 expression by immunohistochemistry in a well characterized cohort of 59 PDAC and 18 peritumoral tissues. Despite the histopathological homogeneity within our cohort, tumor tissues exhibited a great heterogeneity regarding PD-L1 expression. Considering distinct PD-L1 expression patterns, we established the novel POLE Score that incorporates overall PD-L1 expression (P), cellular Origin of PD-L1 (O), PD-L1 level in tumor-associated Lymph follicles (L) and Enumerated local PD-L1 distribution (E). We show that tumoral PD-L1 expression is higher compared to peritumoral areas. Furthermore, POLE Score parameters correlated with overall survival, tumor grade, Ki67 status, local proximity of tumor cells and particular stroma composition. For the first time, we demonstrate that PD-L1 is mostly expressed by stroma and rarely by tumor cells in PDAC. Moreover, our in situ analyses on serial tissue sections and in vitro data suggest that PD-L1 is prominently expressed by tumor-associated macrophages. In conclusion, POLE Score represents a comprehensive characterization of PD-L1 expression in tumor and stroma compartment and might provide the basis for improved patient stratification in future clinical trials on PD-1/PD-L1 targeting therapies in PDAC.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer related deaths in Western countries [1]
Supporting the assumption that genomic alterations acquired during malignant transformation might cause the ability for aberrant programmed death 1 ligand 1 (PD-L1) expression in pancreatic ductal epithelial cells, we showed that ducts in peritumoral tissues lack PD-L1 expression and that most PDAC cell lines were characterized by low PD-L1 expression
This study provides a detailed characterization of PD-L1 expression in PDAC and indicates that PD-L1 expression and its tumor biological relevance have to be rated context dependent, but individual consideration of PD-L1 status might not be applicable for stratification of PDAC patients
Summary
Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer related deaths in Western countries [1]. More than 80% of PDAC patients are diagnosed www.oncotarget.com at locally advanced or metastatic stages [2]. Despite the advances in research on PDAC development and progression, palliative chemotherapy represents the only treatment option for patients with unresectable tumors [3]. The extensive desmoplastic stroma, which constitutes almost 80% of the tumor mass, has been shown to promote aggressiveness and treatment resistance of PDAC [4]. Immunotherapeutical approaches are promising novel strategies to reactivate tumor directed immune responses. Based on the impressive response rates in several other malignancies, e.g. non-small cell lung carcinoma and melanoma, blocking of the programmed cell death protein 1 (PD-1)/programmed cell death 1 ligand 1 (PD-L1) signaling pathway currently represents one the most intensively investigated immune therapies for the treatment of PDAC [7]
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