POLE Score: a comprehensive profiling of programmed death 1 ligand 1 expression in pancreatic ductal adenocarcinoma

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.

Unique Spatial Immune Profiling in Pancreatic Ductal Adenocarcinoma with Enrichment of Exhausted and Senescent T Cells and Diffused CD47-SIRPα Expression

“…In our study we employed SP263 and 28-8 clones which are both validated to examine PD-L1 staining in human tumor samples. Our work correlates with previous studies employing E1L3N clone to study PD-L1 in PDAC patients although the topographical area was not taken into consideration [4,8,26,[33][34][35]. These data suggest that anti-PD-L1/PD-1 monotherapy may have a limited efficacy in PDAC patients.…”

Mechanisms of T-Cell Exhaustion in Pancreatic Cancer

“…Programmed cell death-1 (PD-1), mostly expressed on effector CD4+ Th cells and CD8+ TILs [ 90 , 97 , 98 , 99 ], binds to its ligands, PD-L1 and PD-L2, on solid tumors [ 100 ], on tumor-infiltrating dendritic cells [ 101 ], and on tumor associated-macrophages and MDSCs [ 102 ], to prevent chronic activation of T cells [ 15 ] ( Figure 2 ). If antigen-overexposure occurs, PD-1/PD-L1 signaling creates a positive feedback loop where this signaling becomes dominant and generates an exhausted T-cell population within the tumor and its periphery by inhibiting T-cell activation upon the recruitment of SHP2 tyrosine phosphatase which dephosphorylates CD28, attenuating TCR signaling [ 103 ].…”

“…If antigen-overexposure occurs, PD-1/PD-L1 signaling creates a positive feedback loop where this signaling becomes dominant and generates an exhausted T-cell population within the tumor and its periphery by inhibiting T-cell activation upon the recruitment of SHP2 tyrosine phosphatase which dephosphorylates CD28, attenuating TCR signaling [ 103 ]. PDAC is described as ‘immunologically cold’ compared to highly immunogenic melanoma because of very low surface presentation of neoantigens, and the insufficient Tc infiltration into the tumor core because of fibrotic trap and TAMs localized in the surrounding of tumor [ 3 , 55 , 102 , 104 ] which result in poor clinical outcomes from immune-checkpoint inhibitors targeting PD-1/PD-L1 and CTLA-4 [ 70 , 105 , 106 ]. A comprehensive retrospective study on resected PDAC tumors reported four major subclasses of tumors based on genomic, transcriptomic and, clinicopathological data.…”

Tumor resistance mechanisms and their consequences on γδ T cell activation

“…Although significant improvement has been obtained such novel biological therapies, many patients do not experience clinical benefit due to other tumor resistance mechanisms. [5][6][7][8] These mechanisms negatively influence T cell effector function including the anti-tumor response of γδ T cells.…”