Correlation between tumor infiltrating immune cells and peripheral regulatory T cell determined using methylation analyses and its prognostic significance in resected gastric cancer

PLoS One. 2021 Jun 4;16(6):e0252480. doi: 10.1371/journal.pone.0252480. eCollection 2021.

Abstract

Peripheral regulatory T cells (pTregs) are a highly immunosuppressive fraction of CD4+ T cells. We aimed to evaluate the clinical significance of pTregs in patients with gastric cancer and to determine the correlation between pTregs and immune cell infiltration in tumor microenvironment. pTregs status was determined by assessing the pTreg/total T-cell ratio (ratio of Foxp3 Treg-specific demethylated region (TSDR) to CD3G/CD3D demethylation, so-called Cellular Ratio of Immune Tolerance "ImmunoCRIT") using methylation analyses in 433 patients with gastric cancer who received curative surgery. Among 422 evaluable patients, 230 (54.5%) had high ImmunoCRIT (> 21.0). Patients with high ImmunoCRIT had significantly shorter disease-free survival (DFS) and overall survival (OS) than those with high ImmunoCRIT (p = 0.030, p = 0.008, respectively). In multivariate analysis, high ImmunoCRIT kept a prognostic role for shorter OS (hazard ratio [HR] 1.9, 95% confidence interval [CI] 1.4-2.9; p = 0.005). CD3+ cell density and CD4+ cell density was significantly higher within the tumor in high ImmunoCRIT group than those in low ImmunoCRIT group (CD3+ cell, 202.12/mm2 vs. 172.2/mm2, p = 0.029; CD4+ cell, 56.5/mm2 vs. 43.5/mm2, p = 0.007). In conclusion, the peripheral ImmunoCRIT determined by epigenetic methylation analysis provides prognostic information in resected gastric tumors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Biomarkers, Tumor / genetics*
  • Biomarkers, Tumor / immunology
  • DNA Methylation*
  • Female
  • Humans
  • Lymphocyte Subsets
  • Male
  • Middle Aged
  • Stomach Neoplasms / genetics*
  • Stomach Neoplasms / immunology
  • Stomach Neoplasms / pathology
  • Stomach Neoplasms / surgery
  • T-Lymphocytes, Regulatory / immunology*
  • Tumor Microenvironment

Substances

  • Biomarkers, Tumor

Grants and funding

This study was supported by grant no. 14-2014-009 from the SNUBH research fund.