Critical role of spatial interaction between CD8+ and Foxp3+ cells in human gastric cancer: the distance matters

Abstract

Purpose

In various cancer types, an abundance of FoxP3+ regulatory T cells (Treg) has been associated with an unfavorable outcome. Yet, the role of Treg on cancer immunity has been shown to be complex. In single cell marker technique, other tumor-infiltrating lymphocytes (TILs) such as cytotoxic CD8+ T cells (CTL) also influenced prognosis. This study for the first time investigates the concurrent spatial distribution pattern of CD8+ and FoxP3+ TILs and their prognostic impact in human gastric cancer.

Materials and methods

Tumor tissue microarrays of 50 patients with surgically treated adenocarcinoma of the cardia were studied. An immunohistochemical double staining of CD8+ and FoxP3+ TILs was performed. Cell counts and cell-to-cell distances in tumor epithelium and stroma were evaluated with image-processing software. Metastasis-free survival, no-evidence-of-disease survival, and overall survival were investigated (mean follow-up time 6.9 years).

Results

High intraepithelial infiltration of CD8+ and FoxP3+ TIL was associated with the improved 10-year metastasis-free survival (83 vs. 54 %, p = 0.04 and 85 vs. 59 %, p = 0.09, respectively). Considering cell-to-cell distance and comparing patients with functional (30–110 μm) versus nonfunctional distances of CD8+ and FoxP3+ TILs, 10-year survival rates differed between 89 and 55 % (p = 0.009), respectively.

Conclusion

Prognostic influence of tumor-infiltrating immune cells in gastric cancer critically depends on their cell-to-cell distance. FoxP3+ TILs must be located within a distance between 30 and 110 μm of CD8+ T cells to positively impact on prognosis.

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Acknowledgments

We thank Christa Winkelmann for excellent technical assistance.

Conflict of interest

The authors declare that they have no conflict of interest.

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Correspondence to Luitpold V. Distel.

Additional information

Anita Feichtenbeiner and Matthias Haas have contributed equally to this work.

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Feichtenbeiner, A., Haas, M., Büttner, M. et al. Critical role of spatial interaction between CD8+ and Foxp3+ cells in human gastric cancer: the distance matters. Cancer Immunol Immunother 63, 111–119 (2014). https://doi.org/10.1007/s00262-013-1491-x

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Keywords

  • Regulatory T cells
  • Cytotoxic T cells
  • Tumor-infiltrating lymphocytes
  • Gastric cancer
  • Cancer immunology
  • Immune evasion