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TM9SF2 Reprograms Antigen Presenting Neutrophils to Overcome Immune Evasion in NSCLC

ABSTRACT: Immune evasion drives resistance to immunotherapy in non-small cell lung cancer (NSCLC), but the underlying mechanisms remain incompletely understood. Through a surfaceome-focused CRISPR screen, we identified Tm9sf2 as a critical regulator of immune evasion in NSCLC. We demonstrate that Tm9sf2 sustains an MHC I/II-mediated antigen-presenting Il15rahigh neutrophil subset, which is essential for T cell infiltration and activation. Mechanistically, Tm9sf2 deficiency disrupts nuclear translocation of the NuRD transcriptional repressor complex, leading to derepression of Col6a1 and its pathological hypersecretion into the tumor microenvironment. Subsequently, Col6a1 binds to the surface receptor Tlr4 on neutrophils, activating the Stat3-Socs1 axis to suppress interferon signaling and impair antigen presentation, thereby abrogating neutrophil- and T cell-mediated anti-tumor immunity. Therapeutically, amitriptyline restores Tm9sf2 expression while inhibiting Col6a1 production, thereby expanding the antigen-presenting Il15rahigh neutrophil subset to reignite anti-tumor T cell responses. These findings delineate a previously unrecognized immune evasion axis in NSCLC and identify a potential strategy to reverse immunotherapy resistance.

ORGANISM(S): Mus musculus

PROVIDER: GSE305250 | GEO | 2026/09/01

REPOSITORIES: GEO

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Project description:Non-small cell lung cancer (NSCLC) is a major cause of cancer-associated mortality worldwide, and bone metastasis is the most prevalent event observed in patients with advanced NSCLC. However, the pathogenesis of bone metastases has not been fully elucidated. In the present study, differentially expressed genes (DEGs) were identified by gene expression microarray analysis of NSCLC tissue samples with or without bone metastases. Subsequently, collagen family collagen 6A1 (COL6A1) was chosen as the target gene through Ingenuity Pathway Analysis and reverse transcription-quantitative (RT-q)PCR validation of the top eight DEGs. COL6A1 was overexpressed or knocked down, and the proliferation and invasion of NSCLC cells was assessed using Cell Counting Kit-8, colony formation and Transwell invasion assays. Additionally, the osteogenic capacity of HOB and hES-MP 002.5 cells was assessed using RT-qPCR, western blotting, Alizarin Red staining and alkaline phosphatase staining. A total of 364 DEGs were identified in NSCLC tissues with bone metastases compared with NSCLC tissues without bone metastases, including 140 upregulated genes and 224 downregulated genes. Gene Ontology analysis indicated that the upregulated and downregulated genes were primarily enriched in ‘cellular process’, ‘metabolic process’ and ‘biological regulation’. Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis revealed that the upregulated genes were primarily enriched in ‘cysteine and methionine metabolism’, ‘oxidative phosphorylation’ and the ‘ribosome’, while the downregulated genes were primarily enriched in ‘transcriptional mis-regulation in cancer’, ‘ribosome’ and ‘mitophagy in animals’. COL6A1 was highly expressed in NSCLC tissue samples with bone metastases. Functionally, COL6A1 overexpression induced the proliferation and invasion of HARA cells, and knockdown prevented the proliferation and invasion of HARA-B4 cells. Finally, it was demonstrated that HOB and hES-MP 002.5 cells exhibited osteogenic capacity, and overexpression of COL6A1 in HARA cells increased adhesion of these cells to the osteoblasts, whereas knockdown of COL6A1 in HARA-B4 cells reduced their adhesive ability. In conclusion, COL6A1 may serve as a potential diagnostic marker and therapeutic target for bone metastasis in NSCLC.

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TM9SF2 Reprograms Antigen Presenting Neutrophils to Overcome Immune Evasion in NSCLC

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