Abstract
Immune checkpoint inhibitors (ICIs) targeting PD-1 improve outcomes in advanced non-small cell lung cancer (NSCLC), but responses are heterogeneous and tissue biomarkers are imperfect. Circulating immunoglobulins integrate B- and T-cell function and may reflect systemic immune competence. We investigated whether plasma immunoglobulin levels during ICI therapy are associated with clinical outcomes in stage IV NSCLC. In this single-center retrospective study, 55 patients received anti-PD-1-based regimens: anti-PD-1 monotherapy (n = 31), chemotherapy plus anti-PD-1 (n = 18), or ipilimumab plus nivolumab (n = 6). Plasma IgG, IgA, and IgM were measured at baseline and after 1–4 cycles, and associations with objective response, progression-free survival (PFS), and overall survival (OS) were evaluated. In the chemotherapy plus anti-PD-1 group, IgG decreased significantly on treatment (p = 0.0030), whereas no significant changes in any isotype were observed with anti-PD-1 monotherapy. In the monotherapy cohort, post-treatment IgG was higher in responders than in non-responders (p = 0.0262) and was associated with longer PFS (p = 0.0218) and OS (p = 0.0166). In multivariable Cox models in the monotherapy cohort, higher post-treatment IgG remained independently associated with longer PFS (adjusted HR 0.28, 95% CI 0.11–0.75; p = 0.011) and OS (adjusted HR 0.29, 95% CI 0.09–0.87; p = 0.028). Sensitivity analyses incorporating PD-L1 status and 6-week landmark analyses showed similar trends. In exploratory pooled analyses, no significant association between post-treatment IgG and PFS or OS was observed across all 55 patients. IgA and IgM were not significantly associated with outcomes. Higher early on-treatment plasma IgG may serve as a non-invasive biomarker of favorable outcome, particularly in the anti-PD-1 monotherapy setting, warranting prospective validation and mechanistic studies.
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Conceptualization: RO, SW; Methodology: RO, NO, MW, JJ, and SW; Investigation: RO, HA, MS, GI, TI, RS, TT, TK, KY, TT, HA, and SW; Formal analysis: RO, NO, MW, JJ, and SW; Validation: RO, SW; Writing – original draft: RO; Writing – review & editing: RO, SK, TT, AH, and SW; Supervision: SK, TT, AH, and SW. All authors have read and approved the final version of the manuscript.
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This retrospective study was approved by the Ethics Committee of the Showa Medical University School of Medicine, Tokyo, Japan (approval numbers M2165 and M2253).
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Ohkuma, R., Onishi, N., Watanabe, M. et al. Elevated plasma IgG is associated with improved treatment response and survival in advanced non‑small cell lung cancer patients treated with anti‑PD‑1 therapy. Sci Rep (2026). https://doi.org/10.1038/s41598-026-46923-x
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DOI: https://doi.org/10.1038/s41598-026-46923-x
