WCLC 2025 - Posters & ePosters-P3.03.16 CXCR2+ Neutrophils Influence Immunotherapy Efficacy in NSCLC Patients With KL Subtype

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This study investigates the role of CXCR2-expressing tumor-associated neutrophils (TANs) in influencing immunotherapy efficacy in non-small cell lung cancer (NSCLC) patients with KRAS mutations, focusing on the KL subtype (concurrent KRAS mutation and LKB1 deletion), which typically shows poor immunotherapy response.<br /><br />A retrospective analysis was conducted on 294 advanced NSCLC patients harboring KRAS mutations who received immunotherapy at Shanghai Pulmonary Hospital from 2022 to 2024. Among them, 26 had next-generation sequencing data: 16 were KP subtype (KRAS + TP53 mutation), 3 were KL subtype, and 7 had other mutations. The objective response rate (ORR) to immunotherapy was 62.5% in KP, 0% in KL, and 14.3% in others, confirming KL subtype refractoriness.<br /><br />RNA sequencing and single-cell RNA sequencing analyses of tumor tissue revealed that KL tumors had significantly higher infiltration of TANs, particularly a CXCR2+ neutrophil subset. These CXCR2+ neutrophils expressed immunosuppressive factors such as TGF-β and IL-10. Additionally, gene set enrichment analysis showed upregulation of cytokine and chemokine pathways, with CXCL3 notably increased in KL tumors. RT-PCR confirmed elevated CXCR2 expression in KL tumors compared to KP tumors.<br /><br />In syngeneic mouse models mimicking KL tumors, combination therapy of a CXCR2 inhibitor and PD-1 monoclonal antibody significantly reduced tumor volume compared to control, suggesting that targeting CXCR2 TANs can improve immunotherapy outcomes.<br /><br />In conclusion, the study highlights that CXCR2+ neutrophil infiltration contributes to immunotherapy resistance in KL subtype NSCLC. Combining CXCR2 inhibition with PD-1 blockade may represent a promising therapeutic strategy to overcome this resistance. This research advances understanding of the tumor immune microenvironment in KRAS-mutant lung cancer and offers potential avenues to enhance immunotherapy efficacy in resistant subtypes.

Asset Subtitle

Xuefei Li

Meta Tag

Speaker Xuefei Li

Topic Tumor Biology – Translational Biology

Keywords

CXCR2

tumor-associated neutrophils

immunotherapy resistance

non-small cell lung cancer

KRAS mutation

KL subtype

PD-1 blockade

CXCR2 inhibitor

tumor microenvironment

single-cell RNA sequencing