Immunophenotype based on inflammatory cells, PD-1/PD-L1 signalling pathway and M2 macrophages predicts survival in gastric cancer

Anna Junttila,Juha P Väyrynen,Sirpa Jalkanen,Jukka-Pekka Mecklin,Istvan Kenessey,Maarit Ahtiainen,Johanna Mrena,Jan Böhm,Ilmo Kellokumpu,Olli Helminen,Teijo Kuopio

doi:10.1038/s41416-020-01053-7

Abstract

BackgroundImmune response against cancer has prognostic impact but its role in gastric cancer is poorly known. The aim of the study was to assess the prognostic significance of immune cell score (CD3+, CD8+), tumour immune escape (PD-L1, PD-1) and immune tolerance (Clever-1).MethodsAfter exclusion of Epstein-Barr virus positive (n = 4) and microsatellite instable (n = 6) tumours, the study included 122 patients with GC undergoing D2 gastrectomy. CD3+ and CD8+ based ICS, PD-L1, PD-1 and Clever-1 expressions were evaluated. Differences in survival were examined using Cox regression adjusted for confounders. The primary outcome was 5-year survival.ResultsThe 5-year overall survival rate was 43.4%. High ICS was associated with improved overall survival (adjusted HR 0.48 (95% CI 0.26–0.87)) compared to low ICS. In the high ICS group, patients with PD-L1 expression (5-year survival 69.2 vs. 53.1%, p = 0.317), high PD-1 (5-year survival 70.6 vs. 55.3% p = 0.312) and high Clever-1 (5-year survival 72.0% vs. 45.5% (p = 0.070) had poor prognosis.ConclusionsHigh ICS was associated with improved survival. In the high ICS group, patients with high PD-L1, PD-1 and Clever-1 had poor prognosis highlighting the importance of immune escape and immune tolerance in GC.

Highlights

Immune response against cancer has prognostic impact but its role in gastric cancer is poorly known
The aim of the present study was to assess the prognostic significance of the host immunity elements in Gastric cancer (GC) by measuring immune cell score (CD3+ and CD8+ cells), Programmed cell death ligand 1 (PD-L1)/programmed death 1 (PD-1) tumour immune escape pathway and immune tolerance mediated by Clever-1 positive M2-like macrophages
The main finding of this study indicates that high immune cell score (ICS) is associated with improved overall survival in GC patients

Summary

Introduction

Immune response against cancer has prognostic impact but its role in gastric cancer is poorly known. Together with the TNM (tumour, node and metastasis) system, it is still used in clinical decision-making and prognostic classification.[2,3] The Cancer Genome Atlas Research Network recently proposed a molecular GC classification into four subtypes: (1) positive for Epstein-Barr virus (EBV), (2) high level of microsatellite instability (MSI), (3) genomically stable and (4) chromosomally unstable, showing that gastric adenocarcinomas comprise diverse molecular backgrounds leading to various clinical courses.[4]. Immunoscore[5] measures densities of CD3+ and CD8+ lymphocytes at the tumour centre and at the invasive margin.[5,6] This has been internationally validated in colorectal cancer and its inclusion as a part of TNM-staging (TNMi) has been proposed, based on findings of greater relative prognostic value than TNM staging.[6] Molecular predictors of survival and therapy response have been intensively researched in GC, but apart from

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