Li Chongwu, Wu Junqi, Zhang Lei, Wang Fang, Xu Long, Zhao Yue, Xiao Yun, Zhuang Fenghui, Hou Likun, Zhao Deping, She Yunlang, Xie Dong, Chen Chang
Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, People's Republic of China.
DeepKinase Co, Ltd., Beijing, People's Republic of China.
JTO Clin Res Rep. 2023 Jul 27;4(9):100556. doi: 10.1016/j.jtocrr.2023.100556. eCollection 2023 Sep.
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.
新辅助化疗免疫疗法最近已成为可切除的局部晚期非小细胞肺癌（NSCLC）的标准治疗方法。然而，影响新辅助免疫疗法疗效的因素仍不明确。已发现代谢物可调节免疫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。
纳入在一项前瞻性2期临床试验（NCT04422392）中接受新辅助化疗免疫治疗的IIIA期（N2）NSCLC患者。使用液相色谱-质谱法对治疗前的血浆进行代谢组学分析。进一步使用Lewis肺癌小鼠模型研究潜在机制。对小鼠肿瘤进行蛋白质组学和多重免疫荧光分析。
共纳入39例接受三个周期抗程序性细胞死亡蛋白1（抗PD-1）（信迪利单抗）和化疗的患者。发现未达到主要病理反应的患者中对乙酰氨基酚（APAP）水平显著升高。在多因素逻辑分析中，APAP水平仍然是主要病理反应的独立预测指标。在Lewis肺癌小鼠模型中，与单独使用抗PD-1治疗相比，APAP与抗PD-1联合治疗显著降低了治疗效果。肿瘤蛋白质组学显示，APAP治疗后髓系白细胞激活和中性粒细胞激活途径富集。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证实，联合治疗组中观察到更多的中性粒细胞胞外诱捕网形成。
APAP可通过促进中性粒细胞激活和中性粒细胞胞外诱捕网形成损害NSCLC患者的新辅助化疗免疫治疗疗效。
