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.

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

doi:10.3389/fmed.2020.00144

Abstract

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 (n = 31) and gastric (n = 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 (rs = 0.404, P < 0.0001) and both significantly correlated with CD8+ infiltration (rs = 0.435, P = 0.0003, and rs = 0.444; P = 0.0004, respectively). CD8+ lymphocyte infiltration correlated with improved survival in univariate (P = 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.

Highlights

Gastric and esophageal cancers are major causes of cancerrelated death
Since our earlier studies (Däster et al, unpublished data) indicate that ESCC are poorly infiltrated by immune cells, and considering their highly specific molecular features, in this study we focused on the analysis of gastric and esophageal adenocarcinomas
programmed death 1 (PD-1)/PD-L1 axis plays a crucial role in inhibiting T lymphocyte functions, allowing cancer cells to escape adaptive immune response [4, 5]

Summary

Introduction

Gastric and esophageal cancers are major causes of cancerrelated death. While esophageal cancer is the sixth most common cause of cancer-related death worldwide, gastric cancer is the second, with a high incidence in Asian countries [1]. Localized tumors are routinely treated with surgical resection. Even after potentially curative resection, overall survival (OS) is poor [2, 3], and innovative therapeutic approaches are needed. Interaction of programmed death 1 (PD-1) immune checkpoint protein with its ligands PD-L1 and PD-L2 inhibits anticancer immune responses [4, 5]. The use of immune checkpoint inhibitors has been suggested for gastric and esophageal cancer treatment and different clinical trials have shown promising results [12,13,14,15,16], as recently reviewed [17]. The anti-PD-1 antibody nivolumab (Opdivo R ) is approved in Japan as thirdline treatment for gastric cancer and the anti-PD-1 antibody pembrolizumab (Keytruda R ) recently received FDA approval for the treatment of patients with PD-L1 positive gastric and gastroesophageal junction adenocarcinoma

Methods

Results

Conclusion