AI Article Synopsis

  • Third-generation EGFR-tyrosine kinase inhibitors (EGFR-TKIs) are commonly used to treat patients with EGFR-mutant non-small cell lung cancer (NSCLC), but the factors affecting response or resistance to these treatments remain unclear.
  • This study utilized various advanced techniques such as single-cell RNA sequencing and flow cytometry to analyze tumor samples before and after treatment, revealing that resistant tumors had a significant presence of CXCR1 neutrophils, which were linked to immune suppression and tumor growth.
  • Patients with lower levels of CXCR1 neutrophils prior to treatment had better outcomes, including longer progression-free and overall survival, suggesting that CXCR1 neutrophil infiltration could serve as a predictor for treatment efficacy

Article Abstract

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 and flow 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 19 μm. 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, these findings suggest that CXCR1 neutrophils infiltration was associated with the efficacy of third-generation EGFR-TKI in patients with EGFR-mutant NSCLC.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11621634PMC
http://dx.doi.org/10.1038/s41392-024-02045-2DOI Listing

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