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Background <p>This study aimed to determine the clinicopathologic implications and tumor cell interaction of CD66b-positive (CD66b +) tumor-associated neutrophils (TANs) and CD66b and CD177 double positive (CD66b + /CD177 +) activated TANs in gastric cancer (GC).</p> Methods <p>Single immunohistochemistry (sIHC) for CD66b, CD8, HER2, p53, and E-cadherin was performed in 1,060 patients with GC, together with microsatellite instability (MSI) testing and Epstein-Barr virus (EBV) in situ hybridization. Opal multiplex immunofluorescence (mIF) for cytokeratin (CK), CD66b, and CD177, and sIHC for ERα was performed on 59 microsatellite-stable (MSS) and 60 MSI-high (MSI-H) GCs. The immune cell densities were quantified using QuPath for sIHC and InForm for mIF.</p> Results <p>On sIHC, a high density of CD66b + TANs was correlated with HER2 positivity, EBV positivity, and MSI-H phenotype (<i>p</i> &lt; 0.001). Combined analysis of CD66b + TAN densities in the tumor center and invasive margin showed a significant association with better OS (<i>p</i> = 0.036), independent of major clinicopathologic factors. TAN densities were significantly associated with OS in female patients (<i>p</i> &lt; <i>0.001</i>), but not in male patients (<i>p</i> = <i>0.574</i>). The density of ERα-positive immune cells was inversely correlated with TAN density (ρ = -0.41, <i>p</i> &lt; <i>0.001</i>). mIF analysis demonstrated that both CD66b + TANs and CD66b + /CD177 + activated TANs were significantly more abundant in MSI-H GC than in MSS GC. Moreover, the distance between TANs and CK + GC cells was significantly shorter in MSI-H GC than in MSS GC. A shorter distance between CD66b + /CD177 + activated TANs and GC cells was also associated with a better OS (<i>p</i> = 0.041).</p> Conclusion <p>A high TAN density in GC is associated with a favorable prognosis, and the spatial proximity of TANs to GC cells, especially in MSI-H GC, provides additional prognostic value. These findings provide basic knowledge for the development of therapeutic targets related to TANs in GC.</p>

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Prognostic significance and tumor cell interactions of tumor-associated neutrophils in gastric cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月9日

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  • Soo Kyung Nam,
  • Seo Hwan Yu,
  • Sun-Young Ahn,
  • Yujun Park,
  • Hyeon Jeong Oh,
  • Yoonjin Kwak,
  • Seong-Ho Kong,
  • Do Joong Park,
  • Hyuk-Joon Lee,
  • Han-Kwang Yang,
  • Hye Seung Lee

摘要

Background

This study aimed to determine the clinicopathologic implications and tumor cell interaction of CD66b-positive (CD66b +) tumor-associated neutrophils (TANs) and CD66b and CD177 double positive (CD66b + /CD177 +) activated TANs in gastric cancer (GC).

Methods

Single immunohistochemistry (sIHC) for CD66b, CD8, HER2, p53, and E-cadherin was performed in 1,060 patients with GC, together with microsatellite instability (MSI) testing and Epstein-Barr virus (EBV) in situ hybridization. Opal multiplex immunofluorescence (mIF) for cytokeratin (CK), CD66b, and CD177, and sIHC for ERα was performed on 59 microsatellite-stable (MSS) and 60 MSI-high (MSI-H) GCs. The immune cell densities were quantified using QuPath for sIHC and InForm for mIF.

Results

On sIHC, a high density of CD66b + TANs was correlated with HER2 positivity, EBV positivity, and MSI-H phenotype (p < 0.001). Combined analysis of CD66b + TAN densities in the tumor center and invasive margin showed a significant association with better OS (p = 0.036), independent of major clinicopathologic factors. TAN densities were significantly associated with OS in female patients (p < 0.001), but not in male patients (p = 0.574). The density of ERα-positive immune cells was inversely correlated with TAN density (ρ = -0.41, p < 0.001). mIF analysis demonstrated that both CD66b + TANs and CD66b + /CD177 + activated TANs were significantly more abundant in MSI-H GC than in MSS GC. Moreover, the distance between TANs and CK + GC cells was significantly shorter in MSI-H GC than in MSS GC. A shorter distance between CD66b + /CD177 + activated TANs and GC cells was also associated with a better OS (p = 0.041).

Conclusion

A high TAN density in GC is associated with a favorable prognosis, and the spatial proximity of TANs to GC cells, especially in MSI-H GC, provides additional prognostic value. These findings provide basic knowledge for the development of therapeutic targets related to TANs in GC.