Programmed cell death-ligand 1 expression predicts survival in patients with gastric carcinoma with microsatellite instability.

Junhun Cho,Se Hoon Park,Jeeyun Lee,Jae Moon Bae,Won Ki Kang,Joon Ho Lee,Min Gew Choi,Kyoung-Mee Kim,Seung Tae Kim,Sung Kim,Heejin Bang,Tae Sung Sohn,Ji Yeong An

doi:10.18632/oncotarget.14519

Abstract

Programmed death-ligand 1 (PD-L1) is expressed in a subgroup of gastric cancers that may benefit from immunotherapy. Microsatellite instability-high (MSI-H) is a potential predictive factor for response to immunotherapy targeting the PD-1 or its ligand PD-L1. The relationship between PD-L1 expression and MSI-H status remains poorly understood. In this study, we investigated PD-L1 expression in patients with MSI-H gastric cancer. We analyzed PD-L1 expression in 78 MSI-H gastric cancer tissue samples using immunohistochemistry. PD-L1 expression was classified as expression on tumor cells or on immune cells. We observed PD-L1 expression in 48 gastric cancer samples (61.5%), consisting of 7 (9.0%) cases with tumor PD-L1 expression and 47 (60.3%) cases with immune cell PD-L1 expression. Immune cell PD-L1 expression was frequently associated with intestinal type cancer by the Lauren classification (p = 0.015), with a lower risk of lymph node metastasis (p = 0.027) and lower tumor stages (p = 0.029) compared to MSI-H gastric cancers without PD-L1 expression. Moreover, immune cell PD-L1 expression was an independent favorable prognostic factor for overall survival (versus PD-L1 negative; hazard ratio, 3.451; 95% confidence interval, 1.172–12.745; p = 0.025). In MSI-H gastric cancer, PD-L1 expression was observed to be independently associated with a longer survival.

Highlights

Gastric cancer is the fourth most commonly diagnosed cancer and the second leading cause of cancerrelated mortality worldwide [1]
Previous studies have shown that the expression of Programmed death-ligand 1 (PD-L1) is linked with a worse prognosis in patients with cancer compared with those without PD-L1 expression; this finding remains controversial in case of some cancers [15]
We investigated the clinicopathological characteristics of PD-L1 expression in patients with Microsatellite instability-high (MSI-H) gastric carcinoma and found that PD-L1 expression was an independent prognostic factor for the survival of such patients

Summary

Introduction

Gastric cancer is the fourth most commonly diagnosed cancer and the second leading cause of cancerrelated mortality worldwide [1]. Microsatellite instability-high (MSI-H) tumors, is associated with elevated mutation rates including mutations in genes encoding targetable oncogenic signaling proteins [4]. A hypothesis has been proposed that cancers with a high prevalence of somatic mutations due to mismatch-repair defects may be susceptible to immune checkpoint blockade [12]. A phase 2 clinical trial for evaluating the clinical activity of pembrolizumab, the first programmed death 1 (PD-1) inhibitor, revealed that patients with MSI-H www.impactjournals.com/oncotarget colorectal carcinomas and high somatic mutation loads are associated with better prognosis than patients with microsatellite stable (MSS) cancer [13]. Previous studies have shown that the expression of PD-L1 is linked with a worse prognosis in patients with cancer compared with those without PD-L1 expression; this finding remains controversial in case of some cancers [15]. In the majority of studies, PD-L1 expression was associated with an unfavorable prognosis [16,17,18,19,20,21,22, 25, 26]; recent studies have linked PD-L1 expression with a favorable prognosis [23, 24]

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Conclusion