Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Republic of Korea.
Yonsei Biomedical Research Institute, College of Medicine, Yonsei University, Seoul, Republic of Korea.
PLoS One. 2021 Jun 4;16(6):e0252480. doi: 10.1371/journal.pone.0252480. eCollection 2021.
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.
外周调节性 T 细胞（pTregs）是 CD4+T 细胞中具有高度免疫抑制作用的细胞群。我们旨在评估胃癌患者外周 pTregs 的临床意义，并确定其与肿瘤微环境中免疫细胞浸润的相关性。我们通过甲基化分析评估了 433 例接受根治性手术的胃癌患者外周 pTregs 状态，采用 Foxp3 Treg 特异性去甲基化区域（TSDR）与 CD3G/CD3D 去甲基化的 pTreg/总 T 细胞比值（所谓的免疫耐受细胞比“ ImmunoCRIT”）来确定 pTregs 状态。在 422 例可评估的患者中，有 230 例（54.5%）的 ImmunoCRIT 较高（>21.0）。与 ImmunoCRIT 较高的患者相比，ImmunoCRIT 较高的患者无疾病生存（DFS）和总生存（OS）明显更短（p=0.030，p=0.008）。多变量分析显示，高 ImmunoCRIT 与 OS 较短具有预后作用（风险比[HR]1.9，95%置信区间[CI]1.4-2.9；p=0.005）。与 ImmunoCRIT 较低的患者相比，ImmunoCRIT 较高的患者肿瘤内 CD3+细胞密度和 CD4+细胞密度明显更高（CD3+细胞，202.12/mm2 比 172.2/mm2，p=0.029；CD4+细胞，56.5/mm2 比 43.5/mm2，p=0.007）。总之，通过表观遗传甲基化分析确定的外周 ImmunoCRIT 可为切除的胃肿瘤提供预后信息。
