Cancer Medicine Department, Gustave Roussy, Villejuif, France; Medical Oncology Department, Hospital Clínic, Barcelona, Spain; Translational Genomics and Targeted Therapeutics in Solid Tumors, August Pi I Sunyer Biomedical Research Institute, Barcelona, Spain. Electronic address: https://twitter.com/LauraMezquitaMD.
Department of Medicine, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center NY, USA.
Eur J Cancer. 2021 Jul;151:211-220. doi: 10.1016/j.ejca.2021.03.011. Epub 2021 May 19.
dNLR at the baseline (B), defined by neutrophils/[leucocytes-neutrophils], correlates with immune-checkpoint inhibitor (ICI) outcomes in advanced non-small-cell lung cancer (aNSCLC). However, dNLR is dynamic under therapy and its longitudinal assessment may provide data predicting efficacy. We sought to examine the impact of dNLR dynamics on ICI efficacy and understand its biological significance.
aNSCLC patients receiving ICI at 17 EU/US centres were included [Feb/13-Jun/18]. As chemotherapy-only group was evaluated (NCT02105168). dNLR was determined at (B) and at cycle2 (C2) [dNLR≤3 = low]. B+C2 dNLR were combined in one score: good = low (B+C2), poor = high (B+C2), intermediate = other situations. In 57 patients, we prospectively explored the immunophenotype of circulating neutrophils, particularly the CD15+CD244-CD16cells (immature) by flow cytometry.
About 1485 patients treatment with ICI were analysed. In ICI-treated patients, high dNLR (B) (~1/3rd) associated with worse progression-free (PFS)/overall survival (OS) (HR 1.56/HR 2.02, P < 0.0001) but not with chemotherapy alone (N = 173). High dNLR at C2 was associated with worse PFS/OS (HR 1.64/HR 2.15, P < 0.0001). When dNLR at both time points were considered together, those with persistently high dNLR (23%) had poor survival (mOS = 5 months (mo)), compared with high dNLR at one time point (22%; mOS = 9.2mo) and persistently low dNLR (55%; mOS = 18.6mo) (P < 0.0001). The dNLR impact remained significant after PD-L1 adjustment. By cytometry, high rate of immature neutrophils (B) (30/57) correlated with poor PFS/OS (P = 0.04; P = 0.0007), with a 12-week death rate of 49%.
The dNLR (B) and its dynamics (C2) under ICI associate with ICI outcomes in aNSCLC. Persistently high dNLR (B+C2) correlated with early ICI failure. Immature neutrophils may be a key subpopulation on ICI resistance.
基线时的中性粒细胞/[白细胞-中性粒细胞]比值（dNLR）与晚期非小细胞肺癌（aNSCLC）患者接受免疫检查点抑制剂（ICI）治疗的结果相关。然而，dNLR 在治疗过程中是动态变化的，其纵向评估可能提供预测疗效的数据。我们旨在研究 dNLR 变化对 ICI 疗效的影响，并了解其生物学意义。
纳入了在 17 个欧洲/美国中心接受 ICI 治疗的 aNSCLC 患者[2013 年 2 月至 2018 年 6 月]（NCT02105168）。作为单纯化疗组进行评估。dNLR 在基线时（B）和第 2 周期（C2）[dNLR≤3=低]确定。B+C2 dNLR 结合在一个评分中：低（B+C2）=良好，高（B+C2）=差，其他情况=中等。在 57 例患者中，我们前瞻性地通过流式细胞术探索了循环中性粒细胞的免疫表型，特别是 CD15+CD244-CD16 细胞（不成熟）。
分析了约 1485 例接受 ICI 治疗的患者。在接受 ICI 治疗的患者中，高 dNLR（B）（约 1/3）与较差的无进展生存（PFS）/总生存（OS）相关（HR 1.56/HR 2.02，P<0.0001），但与单纯化疗无关（N=173）。C2 时的高 dNLR 与较差的 PFS/OS 相关（HR 1.64/HR 2.15，P<0.0001）。当同时考虑两个时间点的 dNLR 时，持续高 dNLR（23%）患者的生存状况较差（mOS=5 个月（mo）），与仅在一个时间点高 dNLR（22%）和持续低 dNLR（55%）相比（mOS=9.2mo）（P<0.0001）。在调整 PD-L1 后，dNLR 的影响仍然显著。通过细胞计数，高比例的不成熟中性粒细胞（B）（30/57）与较差的 PFS/OS 相关（P=0.04；P=0.0007），12 周死亡率为 49%。
ICI 治疗时的 dNLR（B）及其动态变化（C2）与 aNSCLC 患者的 ICI 结果相关。持续高 dNLR（B+C2）与早期 ICI 失败相关。不成熟的中性粒细胞可能是 ICI 耐药的关键亚群。
