AUTHOR=Däster Silvio , Eppenberger-Castori Serenella , Mele Valentina , Schäfer Hannah M. , Schmid Lukas , Weixler Benjamin , Soysal Savas D. , Droeser Raoul A. , Spagnoli Giulio C. , Kettelhack Christoph , Oertli Daniel , Terracciano Luigi , Tornillo Luigi , von Holzen Urs 

TITLE=Low Expression of Programmed Death 1 (PD-1), PD-1 Ligand 1 (PD-L1), and Low CD8+ T Lymphocyte Infiltration Identify a Subgroup of Patients With Gastric and Esophageal Adenocarcinoma With Severe Prognosis

JOURNAL=Frontiers in Medicine

VOLUME=7

YEAR=2020

URL=https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2020.00144

DOI=10.3389/fmed.2020.00144

ISSN=2296-858X

ABSTRACT=<p>Prognosis of gastric and esophageal cancer is poor and treatment improvements are needed. Programmed cell death 1 receptor (PD-1) interaction with its ligand PD-L1 in tumor micro-environment promotes immune tolerance and blocking monoclonal antibodies have entered clinical practice. However, clinical significance of PD-1 and PD-L1 expression in gastric and esophageal adenocarcinomas, particularly in non-Asian patients, is still unclear. Three tissue microarrays including 190 clinically annotated esophageal (<italic>n</italic> = 31) and gastric (<italic>n</italic> = 159) adenocarcinomas and 58 paired mucosa specimens, were stained with PD-1, PD-L1, and CD8-specific reagents in indirect immunohistochemistry assays. PD-L1 expression was detectable in 23.2% of cancer specimens. High PD-1 expression was detectable in 37.3% of cases and high CD8+ infiltration in 76%. PD-L1 and high PD1 expression significantly correlated with each other (<italic>r</italic><sub>s</sub> = 0.404, <italic>P</italic> &lt; 0.0001) and both significantly correlated with CD8+ infiltration (<italic>r</italic><sub>s</sub> = 0.435, <italic>P</italic> = 0.0003, and <italic>r</italic><sub>s</sub> = 0.444; <italic>P</italic> = 0.0004, respectively). CD8+ lymphocyte infiltration correlated with improved survival in univariate (<italic>P</italic> = 0.009), but not multivariate analysis. Most interestingly, multivariate analysis and Kaplan-Meier curves indicate that combined low PD-1/PD-L1 expression and low CD8+ lymphocyte infiltration significantly correlate with poor prognosis. Our data document the clinical significance of a microenvironmental signature including PD-1/PD-L1 expression and CD8+ lymphocyte infiltration in gastric and esophageal adenocarcinomas and contribute to identify a patients' subset requiring more aggressive peri-operative treatments.</p>