Departments of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Dr. Molewaterplein 40, 3015 GD, Rotterdam, The Netherlands.
Department of Urology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands.
Cancer Immunol Immunother. 2023 Mar;72(3):759-767. doi: 10.1007/s00262-022-03250-0. Epub 2022 Aug 17.
PD1 inhibition is effective in patients with metastatic urothelial cancer (mUC), yet a large fraction of patients does not respond. In this study, we aimed to identify a blood-based immune marker associated with non-response to facilitate patient selection for anti-PD1. To this end, we quantified 18 immune cell populations using multiplex flow cytometry in blood samples from 71 patients with mUC (as part of a biomarker discovery trial; NCT03263039, registration date 28-08-2017). Patients were classified as responder (ongoing complete or partial response, or stable disease; n = 25) or non-responder (progressive disease; n = 46) according to RECIST v1.1 at 6 months of treatment with pembrolizumab. We observed no differences in numbers of lymphocytes, T-cells, granulocytes, monocytes or their subsets between responders and non-responders at baseline. In contrast, analysis of ratios of immune cell populations revealed that a high mature neutrophil-to-T-cell ratio (MNTR) exclusively identified non-responders. In addition, the survival of patients with high versus low MNTR was poor: median overall survival (OS) 2.2 vs 8.9 months (hazard ratio (HR) 6.6; p < 0.00001), and median progression-free survival (PFS) 1.5 vs 5.2 months (HR 5.6; p < 0.0001). The associations with therapy response, OS, and PFS for the MNTR were stronger than for the classical neutrophil-to-lymphocyte ratio (HR for OS 3.5, and PFS 3) and the PD-L1 combined positivity score (HR for OS 1.9, and PFS 2.1). In conclusion, the MNTR distinctly and uniquely identified non-responders to treatment and may represent a novel pre-treatment blood-based immune metric to select patients with mUC for treatment with pembrolizumab.
PD1 抑制在转移性尿路上皮癌（mUC）患者中有效，但很大一部分患者没有反应。在这项研究中，我们旨在确定与非反应相关的血液免疫标志物，以促进抗 PD1 的患者选择。为此，我们使用多重流式细胞术在 71 名 mUC 患者的血液样本中定量了 18 种免疫细胞群（作为生物标志物发现试验的一部分；NCT03263039，注册日期 2017 年 8 月 28 日）。根据 RECIST v1.1，患者在接受 pembrolizumab 治疗 6 个月时被分为应答者（持续完全或部分缓解或疾病稳定；n=25）或无应答者（进展性疾病；n=46）。我们在基线时没有观察到应答者和无应答者之间淋巴细胞、T 细胞、粒细胞、单核细胞或其亚群数量的差异。相比之下，免疫细胞群比例的分析表明，高成熟中性粒细胞与 T 细胞比值（MNTR）可以单独识别无应答者。此外，高 MNTR 与低 MNTR 患者的生存情况较差：中位总生存期（OS）分别为 2.2 个月和 8.9 个月（危险比（HR）6.6；p<0.00001），中位无进展生存期（PFS）分别为 1.5 个月和 5.2 个月（HR 5.6；p<0.0001）。MNTR 与治疗反应、OS 和 PFS 的关联强于经典中性粒细胞与淋巴细胞比值（OS 的 HR 为 3.5，PFS 的 HR 为 3）和 PD-L1 联合阳性评分（OS 的 HR 为 1.9，PFS 的 HR 为 2.1）。总之，MNTR 明显且独特地识别了治疗无反应者，可能代表一种新的治疗前血液免疫指标，用于选择 mUC 患者接受 pembrolizumab 治疗。
