Immunologic and transcriptional features associated with long-term response and resistance to immune checkpoint inhibitors in non-small cell lung cancer checkpoint inhibitors in non-small cell lung cancer

Background: Immune checkpoint inhibitors (ICIs) have markedly improved outcomes in non-small cell lung cancer (NSCLC), yet durable benefit is achieved in only a minority of patients. The biological mechanisms underlying tumor response to ICIs-including primary resistance (PriR), acquired resistance (AcqR), and long-term response (LTR)-remain poorly understood. Methods: We reviewed patients with advanced or recurrent NSCLC who initiated first-line ICI monotherapy at the National Cancer Center Hospital (Japan) between 2015-2020. Patients were classified as LTR (defined as progression-free survival ≥48 months), AcqR (initial disease control followed by progression <48 months), or PriR (best response PD). Clinical characteristics were characterized across these groups. Pretreatment tumor RNA-seq data were subjected to transcriptomic analyses. Differential pathway activity was evaluated using Hallmark and Reactome GSEA, and immune-cell composition was inferred using CIBERSORT. Results: A total of 216 patients were included in the clinical cohort. Pretreatment tumor RNA-seq data were available for 46 patients (LTR, n=10; AcqR, n=23; PriR, n=13). Compared with responders (LTR + AcqR), PriR tumors showed marked enrichment of inflammatory and immunosuppressive programs, including IL6-JAK-STAT3, TNFalpha/NF-κB, complement, glycolysis, and hypoxia pathways, suggesting a metabolically stressed and suppressive microenvironment that hinders initial immune activation. In contrast, responders exhibited higher interferon-gamma (IFN-gamma) signaling and T-cell activation signatures. In a direct comparison between LTR and AcqR, LTR tumors uniquely preserved strong IFN-gamma-driven inflammation, intact MHC class I antigen-presentation machinery, and robust cytotoxic and memory T-cell programs. AcqR tumors showed attenuation of antigen-presentation and effector-immune pathways, suggesting that reduced immunogenicity contributes to progression after an initial response. Among PD-L1-high tumors, LTR cases again maintained intact antigen-presentation machinery and sustained IFN-gamma-driven cytotoxic T-cell activity, whereas AcqR tumors demonstrated attenuation of these programs. Conclusion: Compared with PriR and AcqR tumors, LTR tumors showed higher IFN-gamma activity, preserved antigen-presentation activity, and sustained effector T-cell signaling. PriR tumors were characterized by inflammatory and metabolically stressed immunosuppressive programs, whereas AcqR tumors showed loss of antigen-presentation and effector-immune activity after the initial response. These features may help identify patients likely to achieve durable ICI benefit and suggest potential targets to overcome resistance.