新辅助化疗免疫治疗近来已成为可切除的局部晚期非小细胞肺癌的标准治疗。然而，影响新辅助免疫治疗疗效的因素仍然不清楚。发现代谢物能够调节免疫功能，并与晚期肿瘤的免疫治疗疗效相关。因此，我们旨在研究血浆代谢物对新辅助化疗免疫治疗后病理反应的影响。我们纳入了在一项前瞻性2期临床试验（NCT04422392）中接受新辅助化疗免疫治疗的III期A期（N2期）非小细胞肺癌患者。使用液相色谱-质谱联用技术对治疗前的血浆进行代谢组学分析。我们还进一步利用刘易斯肺癌小鼠模型研究了潜在的机制。同时进行了蛋白质组学和多重免疫荧光染色分析。总共纳入了39例接受3个疗程抗PD-1（信立米单抗）和化疗的患者。发现未能获得显著病理学反应的患者血浆中乙酰氨酚（APAP）水平显著升高。经多变量逻辑回归分析发现，APAP水平仍然是显著的病理学反应预测因子。在刘易斯肺癌小鼠模型中，APAP和抗PD-1联合治疗与单独抗PD-1治疗相比，治疗效果明显降低。肿瘤蛋白质组学分析发现在APAP治疗后，骨髓样白细胞活化和中性粒细胞活化途径富集。肿瘤微环境特征分析还显示，联合治疗组具有更丰富的中性粒细胞特征。进一步的多重免疫荧光染色证实在联合治疗组观察到更多的中性粒细胞外陷阱形成。APAP可能通过促进中性粒细胞活化和中性粒细胞外陷阱形成来降低NSCLC患者新辅助化疗免疫治疗的疗效。© 2023 作者。

Neoadjuvant chemoimmunotherapy has recently been the standard of care for resectable locally advanced NSCLC. Factors affecting the neoadjuvant immunotherapy efficacy, however, remain elusive. Metabolites have been found to modulate immunity and associate with immunotherapeutic efficacy in advanced tumors. Therefore, we aimed to investigate the impact of plasma metabolites on the pathologic response after neoadjuvant chemoimmunotherapy.Patients with stage IIIA (N2) NSCLC who underwent neoadjuvant chemoimmunotherapy in a prospective phase 2 clinical trial (NCT04422392) were enrolled. Metabolomic profiling of the plasma before treatment was performed using liquid chromatography-mass spectrometry. A Lewis lung carcinoma mouse model was further used to investigate the underlying mechanisms. Proteomics and multiplexed immunofluorescence of the mice tumor were performed.A total of 39 patients who underwent three cycles of anti-programmed cell death-protein 1 (anti-PD-1) (sintilimab) and chemotherapy were included. The level of acetaminophen (APAP) was found to be significantly elevated in patients who did not achieve major pathologic response. The level of APAP remained an independent predictor for major pathologic response in multivariate logistic analysis. In the Lewis lung carcinoma mouse model, combination of APAP and anti-PD-1 treatment significantly reduced the treatment efficacy compared with anti-PD-1 treatment alone. Proteomics of the tumor revealed that myeloid leukocyte activation and neutrophil activation pathways were enriched after APAP treatment. Tumor microenvironment featuring analysis also revealed that the combination treatment group was characterized with more abundant neutrophil signature. Further multiplexed immunofluorescence confirmed that more neutrophil extracellular trap formation was observed in the combination treatment group.APAP could impair neoadjuvant chemoimmunotherapy efficacy in patients with NSCLC by promoting neutrophil activation and neutrophil extracellular trap formation.© 2023 The Authors.