A. Menarini Biomarkers Singapore Pte Ltd, Singapore, Singapore.
Division of Medical Oncology, National Cancer Centre, Singapore, Singapore.
Cancer Immunol Immunother. 2021 Aug;70(8):2353-2365. doi: 10.1007/s00262-021-02859-x. Epub 2021 Feb 2.
Regulatory T cells (Tregs) are often enriched in tumors, where their immunosuppressive function has a key role in tumor persistence and progression. In colorectal cancer (CRC), however, Tregs are frequently associated with an improved clinical outcome. Tumor-infiltrating Tregs have been shown to exhibit a distinct signature comprising the co-stimulatory molecules (OX40, 4-1BB), cytokine receptors (IL1R2, IL21R, CCR8, CD30), and co-inhibitory molecules (PD-L1, TIGIT). Here, we showed by flow cytometry that circulating CD45RO Tregs from patients with CRC (n = 25) have elevated CD30 and OX40 expression compared to healthy subjects (n = 14). We identified co-expression of CD30 and OX40 on circulating CD45RO Tregs using single-cell images captured by the DEPArray system. The frequency of CD30OX40CD45RO Tregs was significantly higher in CRC patients than in healthy subjects (P < 0.001). Importantly, receiver operating characteristic analysis confirmed that this CD30OX40 Treg subset could strongly discriminate between CRC patients and healthy subjects with the highest accuracy of 92.3%, an AUC of 0.92, a sensitivity of 88%, a specificity of 100%, a positive predictive value of 100%, a negative predictive value of 82.35%, and a trade-off value of 3.44%, compared to other Treg subsets. Consistently, multiplex-IHC/IF of tumor-infiltrating Tregs revealed a significant association between high densities of CD30OX40 Tregs and improved overall survival; no such association was found for other subsets. These data suggest a potential role for CD30OX40 Tregs as a diagnostic or prognostic biomarker in CRC.
调节性 T 细胞 (Tregs) 在肿瘤中常常富集，其免疫抑制功能在肿瘤的持续存在和进展中起着关键作用。然而，在结直肠癌 (CRC) 中，Tregs 常与改善的临床预后相关。已表明肿瘤浸润性 Tregs 表现出独特的特征，包括共刺激分子（OX40、4-1BB）、细胞因子受体（IL1R2、IL21R、CCR8、CD30）和共抑制分子（PD-L1、TIGIT）。在这里，我们通过流式细胞术显示，来自 CRC 患者（n=25）的循环 CD45RO Tregs 与健康受试者（n=14）相比，表达升高的 CD30 和 OX40。我们使用 DEPArray 系统捕获的单细胞图像鉴定了循环 CD45RO Tregs 上 CD30 和 OX40 的共表达。CRC 患者中 CD30OX40CD45RO Tregs 的频率明显高于健康受试者（P<0.001）。重要的是，受试者工作特征分析证实，该 CD30OX40 Treg 亚群能够在 CRC 患者和健康受试者之间进行强烈区分，其准确性最高为 92.3%，AUC 为 0.92，灵敏度为 88%，特异性为 100%，阳性预测值为 100%，阴性预测值为 82.35%，权衡值为 3.44%，与其他 Treg 亚群相比。一致地，肿瘤浸润性 Tregs 的多重免疫荧光/免疫组化显示 CD30OX40 Tregs 密度高与总生存率提高之间存在显著关联；而其他亚群则没有发现这种关联。这些数据表明 CD30OX40 Tregs 作为 CRC 的诊断或预后生物标志物具有潜在作用。
