FOXP3+/CD8+ ratio associated with aggressive behavior in RUNX3-methylated diffuse esophagogastric junction tumor.

IF 5.7 2区 医学 Q1 Medicine Cancer Science Pub Date : 2024-10-23 DOI:10.1111/cas.16373
Suguru Maruyama, Yu Imamura, Tasuku Toihata, Ikumi Haraguchi, Manabu Takamatsu, Makiko Yamashita, Yuichiro Nakashima, Eiji Oki, Kenichi Taguchi, Manabu Yamamoto, Shinji Mine, Akihiko Okamura, Jun Kanamori, Souya Nunobe, Takeshi Sano, Shigehisa Kitano, Tetsuo Noda, Masayuki Watanabe
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Abstract

The tumor immune microenvironment is increasingly becoming a key consideration in developing treatment regimens for aggressive cancers, with evidence that regulatory T cells (Tregs) attenuate the antitumor response by interrupting cytotoxic T cells (CD8+). Here, we hypothesized the prognostic relevance of the proportions of Tregs (marked by forkhead box protein 3 [FOXP3]) and CD8+ cells in diffuse, non-Epstein-Barr virus (EBV)/non-microsatellite instability (MSI)-high gastroesophageal adenocarcinomas (GEAs), which are clinically characterized as more aggressive, immunologically inactive tumors as compared with their intestinal counterparts. Cell-count ratios of FOXP3+/CD8+ expression were calculated at the intratumoral region and invasive margin discretely on digital images from 303 chemo-naive non-EBV/non-MSI-high esophagogastric junction (EGJ) adenocarcinomas. A significant modifying prognostic effect of tumor histology was observed between 5-year EGJ cancer-specific survival and the FOXP3+/CD8+ ratio at the invasive margin in pStage I-III tumors (p for interaction = 0.022; hazard ratio [HR] = 8.47 and 95% confidence interval [CI], 2.04-35.19 for high ratio [vs. low] for diffuse; HR = 1.57 and 95% CI, 0.88-2.83 for high ratio [vs. low] for intestinal). A high FOXP3+/CD8+ ratio at the invasive margin was associated with RUNX3 methylation (p = 0.035) and poor prognosis in RUNX3-methylated diffuse histological subtype (5-year EGJ cancer-specific survival, 52.3% for high and 100% for low, p = 0.015). Multiomics data from The Cancer Genome Atlas linked CCL28 with RUNX3-suppressed diffuse histological subtypes of non-EBV/non-MSI-high GEA. Our data suggest that a high FOXP3+/CD8+ ratio at the invasive margin might indicate tumor immune escape via CCL28, particularly in the RUNX3-methylated diffuse histological subtype.

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FOXP3+/CD8+比率与RUNX3甲基化弥漫性食管胃交界处肿瘤的侵袭行为有关
有证据表明,调节性 T 细胞(Tregs)通过干扰细胞毒性 T 细胞(CD8+)而减弱抗肿瘤反应,因此肿瘤免疫微环境正日益成为开发侵袭性癌症治疗方案的关键考虑因素。在这里,我们假设在弥漫性、非爱伯斯坦-巴尔病毒(EBV)/非微卫星不稳定性(MSI)高的胃食管腺癌(GEA)中,调节性 T 细胞(以叉头盒蛋白 3 [FOXP3]为标志)和 CD8+ 细胞的比例与预后有关。在303例化疗无效的非EBV/非MSI-高食管胃交界处(EGJ)腺癌的数字图像上离散计算了瘤内区域和侵袭边缘的FOXP3+/CD8+表达的细胞计数比。在 p 阶段 I-III 肿瘤中,肿瘤组织学对 5 年 EGJ 癌症特异性生存率和浸润边缘的 FOXP3+/CD8+ 比值有明显的预后调节作用(交互作用 p = 0.022;弥漫型高比值[与低比值]的危险比 [HR] = 8.47,95% 置信区间 [CI]为 2.04-35.19;肠型高比值[与低比值]的危险比 [HR] = 1.57,95% CI 为 0.88-2.83)。浸润边缘的高 FOXP3+/CD8+ 比值与 RUNX3 甲基化(p = 0.035)和 RUNX3 甲基化弥漫组织学亚型的不良预后有关(5 年 EGJ 癌特异性生存率,高比值为 52.3%,低比值为 100%,p = 0.015)。癌症基因组图谱》(The Cancer Genome Atlas)的多组学数据将CCL28与非EBV/非MSI-高GEA的RUNX3抑制弥漫组织学亚型联系起来。我们的数据表明,浸润边缘的高FOXP3+/CD8+比值可能表明肿瘤通过CCL28逃避免疫,尤其是在RUNX3甲基化的弥漫组织学亚型中。
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来源期刊
Cancer Science
Cancer Science ONCOLOGY-
CiteScore
9.90
自引率
3.50%
发文量
406
审稿时长
17 weeks
期刊介绍: Cancer Science (formerly Japanese Journal of Cancer Research) is a monthly publication of the Japanese Cancer Association. First published in 1907, the Journal continues to publish original articles, editorials, and letters to the editor, describing original research in the fields of basic, translational and clinical cancer research. The Journal also accepts reports and case reports. Cancer Science aims to present highly significant and timely findings that have a significant clinical impact on oncologists or that may alter the disease concept of a tumor. The Journal will not publish case reports that describe a rare tumor or condition without new findings to be added to previous reports; combination of different tumors without new suggestive findings for oncological research; remarkable effect of already known treatments without suggestive data to explain the exceptional result. Review articles may also be published.
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