Sexual dimorphism in gastric cancer: tumor-associated neutrophils predict patient outcome only for women

Franziska Clausen,Christoph Röcken,Hans-Michael Behrens,Sandra Krüger

doi:10.1007/s00432-019-03082-z

Franziska Clausen, Christoph Röcken + Show 2 more

Open Access

https://doi.org/10.1007/s00432-019-03082-z

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Abstract

PurposeTumor-associated neutrophils (TANs) are part of the tumor immune microenvironment (TIME) and may contribute to gastric cancer (GC) biology. We hypothesized that TAN are enriched in the TIME, show sex-specific differences, and correlate with patient outcome.MethodsWe analyzed the distribution and putative tumor biological significance of TANs in a well-characterized, therapy-naïve, European GC cohort using immunohistochemical staining of myeloperoxidase (MPO), and digital image analysis using Definiens Tissue Studio®.ResultsDifferent tumor compartments were examined, and TAN densities were correlated with various clinicopathological patient characteristics. TAN density showed a large interindividual variability ranging from 0 to 6711.0 TANs/mm2. Intratumoral distribution patterns were inhomogeneous (tumor surface vs. tumor center vs. invasion front) and correlated significantly with Laurén phenotype, tumor grade, and microsatellite status in the tumor center and invasion front. In the multivariate analysis, TAN density in the invasion front was an independent predictor of tumor-specific survival only for women (HR = 2.77, p < 0.001). In men, no correlation was found between TAN density and survival.ConclusionWith regard to TANs, our study independently validates sexual dimorphism in GC biology.

Highlights

Gastric cancer (GC) is the fifth most common cancer worldwide and the third most common cause of cancer death
Sexual dimorphism in biomedical science is often not addressed and many studies fail to analyze results by sex (Beery and Zucker 2011). To fill this gap of information, and in order to shed further light on tumor immune microenvironment (TIME) and sex-specific differences in GC, we aimed to test the following hypotheses in an European GC cohort: (a) Tumor-associated neutrophils (TANs) in GC are enriched in the TIME; (b) TANs show sex-specific differences; and (c) TAN densities correlate with patient outcome
Sexual dimorphism in immune response capacity relates to differences in immune surveillance competence between men and women, which may contribute to the sex effect observed in malignant tumors (Dorak and Karpuzoglu 2012)

Summary

Introduction

Gastric cancer (GC) is the fifth most common cancer worldwide and the third most common cause of cancer death. Incidence and mortality rates are steadily declining, except for cancers of the cardia and gastroesophageal junction, whose incidence has been stable or even increasing. GC is generally more common in men, and incidence increases with patient age (ENCR 2017; Stewart and Wild 2014). Major risk factors are infection with H. pylori and dietary habits. A minority of GC is linked to Epstein-Barr virus (EBV) infection (Humans 2012).

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