Kuo Yung-Chia, Tai Tzong-Shyuan, Yang Huang-Yu, Lui Kar-Wai, Chao Yin-Kai, Lee Li-Yu, Huang Yenlin, Fan Hsien-Chi, Lin An-Chi, Hsieh Chia-Hsun, Yang Zhangung, Chang Kai-Ping, Lin Chien-Yu, Wang Hung-Ming, Hsu Cheng-Lung
Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, Linkou, Chang Gung University Taoyuan 33305, Taiwan.
Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University Taoyuan 33305, Taiwan.
Am J Cancer Res. 2024 Dec 15;14(12):5717-5733. doi: 10.62347/SSPI9013. eCollection 2024.
Nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus (EBV)-associated cancer, and immune checkpoint inhibitors (ICIs) have shown efficacy in its treatment. The combination of chemotherapy and ICIs represents a new trend in the standard care for metastatic NPC. In this study, we aim to clarify the immune cell profile and related prognostic factors in the ICI-based treatment of metastatic NPC. Programmed cell death ligand 1 (PD-L1) expression was measured in 81 metastatic tissue samples that had not received prior ICI treatment. The combined positive score (CPS) was positive in 58.0% of the samples, with a statistically significant correlation to median overall survival (OS) (CPS ≥ 1 vs. CPS < 1: 28 vs. 16 months, = 0.004). For the combination treatment of metastatic NPC, 62 patients were enrolled in a retrospective analysis, yielding a median OS of 39.3 months. The objective response rate for this combination therapy was 71%, with a complete response rate of 45.2%. With a cutoff value of 4.8 for the pre-treated neutrophil-lymphocyte ratio (NLR) in peripheral blood (PB), the difference in median OS was statistically significant ( = 0.021). Thirty-seven patients received local treatment following the combination therapy of ICIs and chemotherapy, which provided additional survival benefits. Most hyper-responders exhibited a prolonged low NLR (< 3), a high total lymphocyte count, and an undetectable or stable EBV DNA load in PB during treatment. Peripheral blood mononuclear cells (PBMCs) from most patients receiving the combination treatment were rich in PD-1+CD8+ lymphocytes, which showed high expression of both IFN-γ and Granzyme B, demonstrating the ability to kill the EBV-positive NPC cell line and xenografts in vitro and in vivo. Responders also displayed increased levels of CD4+CD45RA-CCR7-CD28+CD57- cells (effector memory cell subset) in peripheral blood. These results indicate that in the context of combined chemotherapy and ICIs, high PD-L1 expression in pre-treated metastatic tumor tissue, a low NLR before treatment, a decrease in NLR after treatment, and local treatment can provide significant benefits for patients with metastatic NPC.
鼻咽癌（NPC）是一种与爱泼斯坦-巴尔病毒（EBV）相关的癌症，免疫检查点抑制剂（ICIs）已在其治疗中显示出疗效。化疗与ICIs联合是转移性NPC标准治疗的新趋势。在本研究中，我们旨在阐明基于ICIs治疗转移性NPC的免疫细胞谱及相关预后因素。在81份未接受过ICI治疗的转移性组织样本中检测程序性细胞死亡配体1（PD-L1）表达。联合阳性评分（CPS）在58.0%的样本中呈阳性，与中位总生存期（OS）具有统计学显著相关性（CPS≥1 vs. CPS<1：28个月vs. 16个月，P = 0.004）。对于转移性NPC的联合治疗，62例患者纳入回顾性分析，中位OS为39.3个月。该联合治疗的客观缓解率为71%，完全缓解率为45.2%。外周血（PB）预处理中性粒细胞与淋巴细胞比值（NLR）的截断值为4.8时，中位OS差异具有统计学显著性（P = 0.021）。37例患者在ICIs与化疗联合治疗后接受了局部治疗，这提供了额外的生存益处。大多数高反应者在治疗期间表现为NLR持续较低（<3）、总淋巴细胞计数较高以及PB中EBV DNA负荷检测不到或稳定。大多数接受联合治疗患者的外周血单个核细胞（PBMCs）富含PD-1+CD8+淋巴细胞，其IFN-γ和颗粒酶B均高表达，证明在体外和体内具有杀伤EBV阳性NPC细胞系和异种移植物的能力。反应者外周血中CD4+CD45RA-CCR7-CD28+CD57-细胞（效应记忆细胞亚群）水平也升高。这些结果表明，在化疗与ICIs联合治疗的情况下，预处理转移性肿瘤组织中高PD-L1表达、治疗前低NLR、治疗后NLR降低以及局部治疗可为转移性NPC患者带来显著益处。
