CXCR1^(+)neutrophil infiltration orchestrates response to thirdgeneration EGFR-TKI in EGFR mutant non-small-cell lung cancer  

作　　者：Haowei Wang Anwen Xiong Xiaoxia Chen Junhong Guo Zhuoran Tang Chunyan Wu Shengxiang Ren Caicun Zhou Jian Chen Likun Hou Tao Jiang 

机构地区：[1]Department of Medical Oncology,Shanghai Pulmonary Hospital&Thoracic Cancer Institute,Tongji University School of Medicine,Shanghai,China [2]Department of Medical Oncology,Shanghai East Hospital,Tongji University School of Medicine,Shanghai,China [3]Department of Pathology,Shanghai Pulmonary Hospital,Tongji University School of Medicine,Shanghai,China [4]Department of Thoracic Surgery,Shanghai Pulmonary Hospital,Tongji University School of Medicine,Shanghai,China

出　　处：《Signal Transduction and Targeted Therapy》2025年第1期278-292,共15页信号转导与靶向治疗(英文)

基　　金：supported in part by grants from the National Natural Science Foundation of China(Nos.82102859,82272875 and 12126605);Shanghai Rising-Star Program(Nos.23QA1408000 and 22QA1407800);Shanghai Science and Technology Innovation Action Plan Medical Innovation Research Program(Nos.23Y11904100 and 21Y11913600);the Health and Family Planning Commission of Shanghai Municipality(No.20224Y0067);Ningbo Top Medical and Health Research Program(No.2022030208);Shanghai Nature Foundation Project(No.21ZR1453200);National Key Clinical Specialty Construction Project,Original exploration project of Shanghai Natural Science Foundation(No.23ZR1480600);Shanghai“Rising Stars of Medical Talent”Youth Development Program Youth Medical Talents-Specialist Program.

摘　　要：Although third-generation Epidermal growth factor receptor—tyrosine kinase inhibitors(EGFR-TKI)is standard of care for patients with EGFR-mutant Non-small cell lung cancer(NSCLC),little is known about the predictors of response or resistance.Here,we integrated single-cell RNA(scRNA)sequencing,bulk RNA sequencing,multiplexed immunofluorescence andflow cytometry data from pretreatment and post-resistant tumor samples of EGFR-mutant NSCLC patients received third-generation EGFR-TKIs.We show that resistant samples had a markedly enriched CXCR1^(+)neutrophils infiltration(P<0.01)than pretreatment samples,which were distinguished from other subtypes of neutrophils and displayed immunosupressive characteristics.Spatial analysis showed that increased CXCR1^(+)neutrophils predominantly infiltrated into the tumor core in resistant samples and the average distance of neutrophils to tumor cells markedly reduced from 33 to 19μm.Deep analysis of scRNA and bulk RNA sequencing data revealed the increased interactions between CXCR1^(+)neutrophils and tumor cells and activated TNF-α/NF-κB signaling pathway in tumor cells of resistant samples.In vitro and in vivo experiments validated that CXCR1^(+)neutrophils resulted in resistance to third-generation EGFR-TKI via activating TNF-α/NF-κB signaling pathway in tumor cells.Importantly,patients with low pretreatment CXCR1^(+)neutrophil infiltration abundance had a dramatically longer progression-free survival(11.8 vs.7.5 months;P=0.019)and overall survival(33.0 vs.23.5 months;P=0.029)than those with high infiltration abundance.Collectively,thesefindings suggest that CXCR1^(+)neutrophils infiltration was associated with the efficacy of third-generation EGFR-TKI in patients with EGFR-mutant NSCLC.

关 键 词：CXCR1 TKI markedly 

分 类 号：R73[医药卫生—肿瘤]