Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan; Department of Next-Generation Surgical Therapy Development, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
Ann Thorac Surg. 2022 Jan;113(1):286-294. doi: 10.1016/j.athoracsur.2021.01.013. Epub 2021 Jan 19.
Immune checkpoint inhibitors targeting the programmed death 1 (PD-1)/programmed death-ligand 1 (PD-L1) pathway have demonstrated antitumor effects in patients with various malignancies, including esophageal cancer. Thus, a better understanding of local immunity in esophageal cancer is crucial for improving treatment and clinical outcomes.
We evaluated PD-1 expression on tumor-infiltrating lymphocytes (TILs), as well as PD-L1 expression on cancer cells, by immunohistochemistry and immunofluorescence using a nonbiased database of 433 curatively resected esophageal cancers. With the idea of application as liquid biopsy, PD-1 expression status on peripheral lymphocytes was evaluated by flow cytometry.
The cutoff value of PD-1 expression was the median PD-1 count. Compared with cases of low PD-1 expression (n = 219), cases with high levels of PD-1 expression (n = 213) showed significantly worse overall survival (log-rank P = .0017). The prognostic effect of PD-1 differed according to the preoperative treatment status (P for interaction = .040); PD-1 expression was associated with high overall mortality among patients without preoperative therapy, while no such association was present among those with preoperative treatment. A stratification based on PD-1 and PD-L1 status was also significantly associated with overall survival (log-rank P = .0005). PD-1 expression on TILs was significantly associated with that on peripheral lymphocytes (P < .0001).
PD-1 expression on TILs was associated with an unfavorable clinical outcome in esophageal cancer, supporting its role as a prognostic biomarker. The combination of PD-1 and PD-L1 expression enabled further classification of patients according to clinical outcome.
针对程序性死亡 1（PD-1）/程序性死亡配体 1（PD-L1）通路的免疫检查点抑制剂已在包括食管癌在内的多种恶性肿瘤患者中显示出抗肿瘤作用。因此，更好地了解食管癌的局部免疫对于改善治疗和临床结局至关重要。
我们通过免疫组化和免疫荧光法，使用 433 例根治性切除的食管癌非偏倚数据库，评估了肿瘤浸润淋巴细胞（TIL）上的 PD-1 表达以及癌细胞上的 PD-L1 表达。为了将其作为液体活检应用，我们通过流式细胞术评估了外周淋巴细胞上 PD-1 的表达状态。
PD-1 表达的截断值为 PD-1 计数的中位数。与低 PD-1 表达（n=219）相比，高 PD-1 表达（n=213）的患者总生存率明显较差（对数秩检验 P=0.0017）。PD-1 的预后作用因术前治疗状态而异（交互检验 P=0.040）；在未接受术前治疗的患者中，PD-1 表达与总死亡率升高相关，而在接受术前治疗的患者中则没有这种关联。基于 PD-1 和 PD-L1 状态的分层与总生存率也显著相关（对数秩检验 P=0.0005）。TIL 上的 PD-1 表达与外周淋巴细胞上的 PD-1 表达显著相关（P<0.0001）。
食管癌中 TIL 上的 PD-1 表达与不良临床结局相关，支持其作为预后生物标志物的作用。PD-1 和 PD-L1 表达的组合可根据临床结局进一步对患者进行分类。
