Institute of Military Cognition and Brain Sciences, Academy of Military Medical Sciences, Beijing, China
Beijing Institute of Basic Medical Sciences, Beijing, China.
J Immunother Cancer. 2023 Mar;11(3). doi: 10.1136/jitc-2022-006462.
Immune checkpoint blockade (ICB) treatment may induce durable disease remission, but only in a minority of patients with cancer. One important question is how to identify patients who may benefit from ICB treatment. ICB treatment relies on unleashing patients' pre-existing immune responses. Focusing on the key components of immune response, this study proposes the neutrophil-to-lymphocyte ratio (NLR) as a simplified indicator of patients' immune status to predict ICB treatment outcomes.
This study analyzed a large pan-cancer cohort of 16 cancer types, including 1714 patients with cancer who received ICB treatment. Clinical outcomes in response to ICB treatment were measured by overall survival (OS), progression-free survival (PFS), objective response rate, and clinical benefit rate. The non-linear relationships of NLR with OS and PFS were investigated by a spline-based multivariate Cox regression model. A total of 1000 randomly resampled cohorts were bootstrapped to estimate the variability and reproducibility of NLR-related ICB responses.
By interrogating a clinically representative cohort, this study revealed a previously unreported finding that the pretreatment NLR levels were associated with ICB treatment outcomes in a U-shaped dose-dependent manner rather than a linear manner. An NLR range between 2.0 and 3.0 was remarkably associated with optimal ICB treatment outcomes, including increased patient survival, delayed disease progression, improved treatment response, and significant clinical benefit. Comparatively, either decreasing (< 2.0) or increasing (>3.0) NLR levels were indicators of worse ICB treatment outcomes. Furthermore, this study presents a comprehensive landscape of NLR-related ICB treatment outcomes across different patient populations defined by demographics, baseline characteristics, treatment, cancer-type-specific ICB responsiveness, and individual cancer type.
The NLR range from 2.0 to 3.0 might indicate an optimal balance between innate (neutrophils) and adaptive (lymphocytes) immune responses that potentiates antitumor immunity, which was observed in only 18.6% of patients. A majority of patients showed decreasing NLR (<2.00; 10.9% patients) or increasing NLR (>3.00; 70.5% patients), representing two distinct types of immune dysregulation associated with ICB resistance. This study translates routine blood tests into a precision medicine-based approach to immunotherapy, with important implications for clinicians in clinical decision-making as well as for regulatory agencies in drug approvals.
免疫检查点阻断（ICB）治疗可能诱导持久的疾病缓解，但仅在少数癌症患者中有效。一个重要的问题是如何识别可能受益于 ICB 治疗的患者。ICB 治疗依赖于释放患者预先存在的免疫反应。本研究关注免疫反应的关键组成部分，提出中性粒细胞与淋巴细胞比值（NLR）作为一种简化的患者免疫状态指标，用于预测 ICB 治疗结果。
本研究分析了一个包含 16 种癌症类型的大型泛癌症队列，其中包括 1714 名接受 ICB 治疗的癌症患者。通过总生存期（OS）、无进展生存期（PFS）、客观缓解率和临床获益率来衡量对 ICB 治疗的临床反应。通过基于样条的多变量 Cox 回归模型研究 NLR 与 OS 和 PFS 的非线性关系。通过 1000 次随机重采样估算 NLR 相关 ICB 反应的可变性和可重复性。
通过检查具有代表性的临床队列，本研究揭示了一个以前未报道的发现，即治疗前 NLR 水平与 ICB 治疗结果呈 U 形剂量依赖性相关，而不是线性相关。NLR 范围在 2.0 到 3.0 之间与最佳 ICB 治疗结果显著相关，包括增加患者生存、延迟疾病进展、改善治疗反应和显著的临床获益。相比之下，NLR 水平降低（<2.0）或升高（>3.0）均提示 ICB 治疗结果较差。此外，本研究还展示了 NLR 相关 ICB 治疗结果在不同患者群体中的全面情况，这些患者群体是根据人口统计学、基线特征、治疗、癌症类型特异性 ICB 反应性和单个癌症类型来定义的。
NLR 范围在 2.0 到 3.0 之间可能表明先天（中性粒细胞）和适应性（淋巴细胞）免疫反应之间的最佳平衡，从而增强抗肿瘤免疫，这仅在 18.6%的患者中观察到。大多数患者的 NLR 降低（<2.00；10.9%的患者）或升高（>3.00；70.5%的患者），这代表了与 ICB 耐药性相关的两种不同类型的免疫失调。本研究将常规血液检查转化为基于精准医学的免疫治疗方法，这对临床医生的临床决策以及监管机构的药物批准都具有重要意义。
