Wu Hui, Shu Wenzhi, Ding Yongfeng, Li Qiong, Li Ning, Wang Qiyue, Chen Yinqi, Han Yuejun, Huang Dongdong, Jiang Haiping
Department of Medical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China.
Zhejiang University School of Medicine, Hangzhou, China.
BMC Cancer. 2025 Aug 25;25(1):1369. doi: 10.1186/s12885-025-14805-6.
Anti-programmed cell death-1 (PD-1) immunotherapy and platinum-based chemotherapy are key components of first-line treatment for advanced Gastric or Gastroesophageal Junction (G/GEJ) cancer. However, the role of immune cells infiltrating the tumor microenvironment (TME) in predicting both therapy responses is still unclear.
ORIENT-16 is a randomized, double-blind, placebo-controlled, phase 3 clinical trial, and enrolled 650 patients with unresectable locally advanced or metastatic G/GEJ cancer between January 3, 2019, and August 5, 2020. For patients enrolled from the First Affiliated Hospital of Zhejiang University School of Medicine, we analyzed progression-free survival(PFS) and overall survival (OS) based on PD-L1 expression and landmark analysis, and developed a multiplexed immunofluorescence (mIF) assay for CD4, CD8, PD-L1, CD68 and FoxP3 coupled with digital image analysis and machine learning to assess prognostic survival associations of immune cells.
A total of 54 eligible patients were enrolled in this study, 35 received sintilimab plus platinum-based chemotherapy and 19 received placebo plus platinum-based chemotherapy. For patients with PD-L1 combined positive score (CPS) < 10, survival disparities between anti-PD-1 immunotherapy and chemotherapy emerged 300 days post-treatment. High PD-L1 expression correlated with longer survival in anti-PD-1 therapy but less benefit in platinum-based chemotherapy. The mIF analysis also demonstrated significantly higher stromal PD-L1 density in immunotherapy responders, but tended to be lower in chemotherapy responders. Besides, high tumor stromal CD8 expression could be used as a positive biomarker in anti-PD-1 immunotherapy, and high tumor stromal CD4 expression was found associated with worse prognosis in platinum-based chemotherapy.
Increased PD-L1 expression was associated with an increased effect on anti-PD-1 immunotherapy and reduced benefit from chemotherapy. The signature of TME immune cells has the potential to predict the response of anti-PD-1 immunotherapy and chemotherapy in G/GEJ cancer.
ClinicalTrials.gov Identifier: NCT03745170.
抗程序性细胞死亡蛋白1（PD-1）免疫疗法和铂类化疗是晚期胃癌或胃食管交界（G/GEJ）癌一线治疗的关键组成部分。然而，肿瘤微环境（TME）中浸润的免疫细胞在预测这两种治疗反应中的作用仍不清楚。
ORIENT-16是一项随机、双盲、安慰剂对照的3期临床试验，于2019年1月3日至2020年8月5日招募了650例不可切除的局部晚期或转移性G/GEJ癌患者。对于从浙江大学医学院附属第一医院招募的患者，我们基于PD-L1表达和标志性分析分析了无进展生存期（PFS）和总生存期（OS），并开发了一种用于CD4、CD8、PD-L1、CD68和FoxP3的多重免疫荧光（mIF）检测方法，结合数字图像分析和机器学习来评估免疫细胞的预后生存关联。
本研究共纳入54例符合条件的患者，35例接受信迪利单抗联合铂类化疗，19例接受安慰剂联合铂类化疗。对于PD-L1联合阳性评分（CPS）<10的患者，抗PD-1免疫疗法和化疗之间的生存差异在治疗后300天出现。高PD-L1表达与抗PD-1治疗的较长生存期相关，但在铂类化疗中获益较少。mIF分析还显示，免疫治疗反应者的基质PD-L1密度显著更高，但化疗反应者的基质PD-L1密度往往更低。此外，高肿瘤基质CD8表达可作为抗PD-1免疫疗法的阳性生物标志物，而高肿瘤基质CD4表达与铂类化疗的较差预后相关。
PD-L1表达增加与抗PD-1免疫疗法的疗效增加和化疗获益减少相关。TME免疫细胞特征有可能预测G/GEJ癌中抗PD-1免疫疗法和化疗的反应。
ClinicalTrials.gov标识符：NCT03745170。
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