Abstract 6460: 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

Abstract 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, TNFα/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-γ (IFN-γ) signaling and T-cell activation signatures. In a direct comparison between LTR and AcqR, LTR tumors uniquely preserved strong IFN-γ-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-γ-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-γ 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. Citation Format: Yoshihiro Masui, Tatsuya Yoshida, Jun Miyakoshi, Ryoko Higashiyama, Akiko Tateishi, Yuki Shinno, Tomonori Mizutani, Yusuke Okuma, Hidehito Horinouchi, Kouya Shiraishi, Takashi Kohno, Yasushi Goto. 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 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6460.