Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan,
Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan,
Oncology. 2022;100(8):419-428. doi: 10.1159/000525239. Epub 2022 Jun 16.
Inducible co-stimulator (ICOS), an important co-stimulatory receptor on effector T cells (Teffs), may also contribute to tumor growth due to its high expression on regulatory T cells (Tregs). This study explored the clinical significance of ICOS-expressing Tregs in hepatocellular carcinoma (HCC).
Tumor tissues from HCC patients who received curative hepatectomy were obtained at a referral center. Dual immunohistochemistry was performed to evaluate the expression of ICOS and Foxp3. The cell densities and proximities between stained cells in regions of interest were measured by digital pathology and the associations with clinical outcome were analyzed.
A total of 142 patients (male:female = 112: 30, median age of 61.0 years) were enrolled. Among them, 87 (61.3%) had chronic hepatitis B virus infection and 33 (23.2%) had chronic hepatitis C infection. Low α-fetoprotein level (<20 ng/mL) and early-stage were significantly associated with improved overall survival (OS). The density of ICOS+Foxp3+ cells and the ratio of ICOS+Foxp3+/total Foxp3+ cells were significantly higher (p < 0.001) in the tumor center than in the peritumor area. Patients with a high density of ICOS+Foxp3+ cells or a high ratio of ICOS+Foxp3+/total Foxp3+ cells in the tumor center trended to have a shorter OS. A shorter distance between ICOS+Foxp3+ cells and ICOS+Foxp3- cells (likely Teffs) in the tumor center was significantly associated with a shorter OS (p = 0.030), suggesting active immunosuppression of ICOS+ Tregs on ICOS+ Teffs.
An increased abundance of ICOS+ Tregs in the tumor center in comparison to the peritumor area indicates a strong immunosuppressive tumor microenvironment of HCC. A high proportion of ICOS+Foxp3+ cells and a shorter distance between ICOS+ Tregs and other ICOS+ cells were associated with a poor OS, suggesting that depleting ICOS+ Tregs might provide clinical benefit for patients with HCC.
诱导共刺激分子（ICOS）是效应 T 细胞（Teffs）上的一种重要共刺激受体，由于其在调节性 T 细胞（Tregs）上的高表达，也可能促进肿瘤生长。本研究探讨了肝癌（HCC）中 ICOS 表达的 Tregs 的临床意义。
在一家转诊中心获得接受根治性肝切除术的 HCC 患者的肿瘤组织。通过双重免疫组织化学评估 ICOS 和 Foxp3 的表达。通过数字病理学测量感兴趣区域中染色细胞的细胞密度和邻近度，并分析与临床结局的关联。
共纳入 142 例患者（男：女=112：30，中位年龄 61.0 岁）。其中，87 例（61.3%）有慢性乙型肝炎病毒感染，33 例（23.2%）有慢性丙型肝炎感染。低甲胎蛋白水平（<20ng/mL）和早期与总生存（OS）改善显著相关。ICOS+Foxp3+细胞的密度和 ICOS+Foxp3+/总 Foxp3+细胞的比例在肿瘤中心显著高于肿瘤周围区域（p<0.001）。肿瘤中心 ICOS+Foxp3+细胞密度高或 ICOS+Foxp3+/总 Foxp3+细胞比例高的患者 OS 趋势较短。肿瘤中心 ICOS+Foxp3+细胞与 ICOS+Foxp3-细胞（可能是 Teffs）之间的距离较短与 OS 较短显著相关（p=0.030），提示 ICOS+Tregs 对 ICOS+Teffs 具有积极的免疫抑制作用。
与肿瘤周围区域相比，肿瘤中心 ICOS+Tregs 的丰度增加表明 HCC 的肿瘤微环境具有强烈的免疫抑制作用。高比例的 ICOS+Foxp3+细胞和 ICOS+Tregs 与其他 ICOS+细胞之间的距离较短与 OS 较差相关，提示耗竭 ICOS+Tregs 可能为 HCC 患者带来临床获益。
