尽管免疫疗法是晚期非小细胞肺癌（NSCLC）的主要治疗方法，但缺乏可靠的临床反应生物标志物。临床反应的异质性以及放射学反应评估对于及时准确预测治疗效果的有限价值（尤其是在疾病稳定的情况下）要求开发分子信息实时微创方法。除了捕获肿瘤消退之外，液体活检还可以为捕获免疫相关不良事件 (irAE) 提供信息。我们研究了接受基于免疫治疗的方案的转移性 NSCLC 患者循环肿瘤 DNA (ctDNA) 的纵向变化。使用 ctDNA 靶向纠错测序以及白细胞和肿瘤组织的匹配测序，我们跟踪了无细胞肿瘤负荷 (cfTL) 的连续变化并确定了分子反应。对外周 T 细胞库动态进行连续评估，并与血浆蛋白表达谱一起进行评估。分子反应（定义为 cfTL 完全清除）与无进展（对数秩 p=0.0003）和总生存期（对数秩）显着相关p=0.01），对于捕捉放射学稳定疾病患者的差异生存结果特别有用。对于出现 irAE 的患者，在临床诊断免疫相关不良事件之前平均 5 个月即可确定治疗中外周血 T 细胞库重塑（通过显着的 TCR 克隆型扩增和回归进行评估）。分子反应有助于解释不同的临床反应，尤其是对于疾病稳定的患者。我们对周围肿瘤和免疫区室的补充评估提供了一种在免疫治疗期间监测临床获益和 irAE 的方法。

Although immunotherapy is the mainstay of therapy for advanced non-small cell lung cancer (NSCLC), robust biomarkers of clinical response are lacking. The heterogeneity of clinical responses together with the limited value of radiographic response assessments to timely and accurately predict therapeutic effect -especially in the setting of stable disease- call for the development of molecularly-informed real-time minimally invasive approaches. In addition to capturing tumor regression, liquid biopsies may be informative in capturing immune-related adverse events (irAEs).We investigated longitudinal changes in circulating tumor DNA (ctDNA) in patients with metastatic NSCLC who received immunotherapy-based regimens. Using ctDNA targeted error-correction sequencing together with matched sequencing of white blood cells and tumor tissue, we tracked serial changes in cell-free tumor load (cfTL) and determined molecular response. Peripheral T-cell repertoire dynamics were serially assessed and evaluated together with plasma protein expression profiles.Molecular response, defined as complete clearance of cfTL, was significantly associated with progression-free (log-rank p=0.0003) and overall survival (log-rank p=0.01) and was particularly informative in capturing differential survival outcomes among patients with radiographically stable disease. For patients who developed irAEs, on-treatment peripheral blood T-cell repertoire reshaping, assessed by significant TCR clonotypic expansions and regressions, was identified on average 5 months prior to clinical diagnosis of an immune-related adverse event.Molecular responses assist with interpretation of heterogeneous clinical responses especially for patients with stable disease. Our complementary assessment of the peripheral tumor and immune compartments provides an approach for monitoring of clinical benefit and irAEs during immunotherapy.