Sex-specific prognostic effect of CD66b-positive tumor-infiltrating neutrophils (TANs) in gastric and esophageal adenocarcinoma

Abstract

Background Tumor-associated neutrophils (TANs) have recently been identified as a relevant component of the tumor microenvironment (TME) in solid tumors. Within the TME TANs mediate either tumor-promoting or tumor-inhibiting activities. So far, their prognostic relevance remains to be determined. This study aims to evaluate the prognostic relevance of TANs in different molecular subtypes of gastric and esophageal adenocarcinoma. Methods We analyzed a total of 1118 Caucasian patients divided into gastric adenocarcinoma (n = 458) and esophageal adenocarcinoma cohort (n = 660) of primarily resected and neoadjuvant-treated individuals. The amount of CD66b + TANs in the tumor stroma was determined using quantitative image analysis and correlated to both molecular, as well as clinical data. Results An accumulation of TANs in the tumor stroma of gastric carcinomas was associated to a significant favorable prognosis (p = 0.026). A subgroup analysis showed that this effect was primarily related to the molecular chromosomal instable subtype (CIN) of gastric carcinomas (p = 0.010). This was only observed in female patients (p = 0.014) but not in male patients (p = 0.315). The same sex-specific effect could be confirmed in adenocarcinomas of the esophagus (p = 0.027), as well as in female individuals after receiving neoadjuvant therapy (p = 0.034). Conclusions Together, we show a sex-specific prognostic effect of TANs in gastric cancer within a Caucasian cohort. For the first time, we showed that this sex-specific prognostic effect of TANs can also be seen in esophageal cancer.

Sex Disparity in Patients with Gastric Cancer: A Systematic Review and Meta-Analysis

“…Female gastric cancer patients had a better prognosis, and this fnding was consistent with most previous studies [9][10][11][12][13][14][15][16][17][18]. Tere are many possible reasons for this phenomenon.…”

“…Studies on the prognosis of gastric cancer in females have produced mixed results. While in most studies, female patients had a better prognosis [9][10][11][12][13][14][15][16][17][18], several other studies showed no independent sex-related associations with OS [19][20][21][22]. Tough some recent studies have found that females had a better overall prognosis, this was not found to be the case in young female patients [23][24][25].…”

The ‘Danse Macabre’—Neutrophils the Interactive Partner Affecting Oral Cancer Outcomes

“…In a European gastric cancer cohort study, immunohistochemical staining of myeloperoxidase was used to show a correlation between TAN density and survival in women but not in men. These findings indicate a possible sex-specific prognostic effect of TANs ( 116 , 117 ). In two independent clinical cohorts, the ratio of CD8 + T cells to TANs within the tumor was associated with anti-PD1 monotherapy failure in non-small cell lung cancer (NSCLC) patients, indicating that neutrophil antagonism may be a sustainable secondary therapeutic approach to boost ICI treatment outcomes ( 118 ).…”

Machine Learning for Future Subtyping of the Tumor Microenvironment of Gastro-Esophageal Adenocarcinomas

“…With more men than women being affected by GEA (6.6 [8.2]/1.8 [3.8], region-specific incidence for age-standardized rates by sex for esophageal cancer [stomach] in 2020, Western Europe [15]), one should also appreciate that sex may be considered as a variable in future trials and clinical management of GEA patients (Figure 1) [76][77][78][79][80]. Given the relevance of sex differences in cancer mortality, molecular and genetically, as well as pharmaceutically, future studies need to define the underlying mechanisms for these differences when studying the TME of GEA [81].…”