Brief Report: Acetaminophen Reduces Neoadjuvant Chemoimmunotherapy Efficacy in Patients With NSCLC by Promoting Neutrophil Extracellular Trap Formation: Analysis From a Phase 2 Clinical Trial

Chongwu Li, MD; Junqi Wu, MD; Lei Zhang, MD; Fang Wang, MD; Long Xu, MD; Yue Zhao, MD; Yun Xiao, PhD; Fenghui Zhuang, MD; Likun Hou, MD, PhD; Deping Zhao, MD, PhD; Yunlang She, MD, PhD; Dong Xie, MD, PhD; Chang Chen, MD, PhD

JTO Clinical and Research Reports (Sep 2023)

Brief Report: Acetaminophen Reduces Neoadjuvant Chemoimmunotherapy Efficacy in Patients With NSCLC by Promoting Neutrophil Extracellular Trap Formation: Analysis From a Phase 2 Clinical Trial

Chongwu Li, MD,
Junqi Wu, MD,
Lei Zhang, MD,
Fang Wang, MD,
Long Xu, MD,
Yue Zhao, MD,
Yun Xiao, PhD,
Fenghui Zhuang, MD,
Likun Hou, MD, PhD,
Deping Zhao, MD, PhD,
Yunlang She, MD, PhD,
Dong Xie, MD, PhD,
Chang Chen, MD, PhD

Affiliations

Chongwu Li, MD: Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, People’s Republic of China
Junqi Wu, MD: Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, People’s Republic of China
Lei Zhang, MD: Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, People’s Republic of China
Fang Wang, MD: Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, People’s Republic of China
Long Xu, MD: Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, People’s Republic of China
Yue Zhao, MD: Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, People’s Republic of China
Yun Xiao, PhD: DeepKinase Co, Ltd., Beijing, People’s Republic of China
Fenghui Zhuang, MD: Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, People’s Republic of China
Likun Hou, MD, PhD: Department of Pathology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, People’s Republic of China
Deping Zhao, MD, PhD: Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, People’s Republic of China
Yunlang She, MD, PhD: Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, People’s Republic of China
Dong Xie, MD, PhD: Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, People’s Republic of China
Chang Chen, MD, PhD: Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, People’s Republic of China; Corresponding author. Address for correspondence: Chan Chen, MD, PhD, Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, People’s Republic of China.

Journal volume & issue: Vol. 4, no. 9
p. 100556

Abstract

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Introduction: 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. Methods: 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. Results: 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. Conclusions: APAP could impair neoadjuvant chemoimmunotherapy efficacy in patients with NSCLC by promoting neutrophil activation and neutrophil extracellular trap formation.

Published in JTO Clinical and Research Reports

ISSN: 2666-3643 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Medicine: Internal medicine: Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Website: https://www.journals.elsevier.com/jto-clinical-and-research-reports/

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