Background Immune checkpoint inhibitors (ICIs) provide durable benefit for a subset of patients with advanced non-small cell lung cancer (NSCLC), however predictive biomarkers remain limited. Peripheral blood offers accessible immune and inflammatory signals that may reflect the onset of systemic mechanisms of resistance. This study aimed to identify circulating immune features associated with clinical outcome and to develop a clinically applicable blood-based score for risk stratification in patients receiving ICIs.Methods Two independent real-world cohorts of advanced NSCLC patients treated with anti-PD-1 therapy were analyzed. Plasma cytokines and chemokines, soluble immune checkpoint molecules and blood cell counts were measured before and during ICI-therapy. Baseline biomarkers associated with progression-free survival (PFS) and overall survival (OS) were incorporated into an Immune-Suppressive Blood Index Score (ISBIS). The ISBIS discriminative performance was first determined in the discovery cohort (n=57) and then validated in an independent cohort (n=56), and nomogram integrating ISBIS with clinical variables was generated.Results ISBIS score predicts poor outcome to be associated with an immunosuppressive blood profile composed of baseline IL-6, IL-8, CCL2, CXCL10, neutrophils, PLR, IFN-gamma and lymphocytes. On-treatment increase in CXCL10, neutrophils, and NLR, as well as decreases in lymphocytes and soluble PD-L2, were associated with early disease progression. ISBIS stratified patients into three risk groups with significantly different survival in both cohorts and remained independently associated to OS. A nomogram combining ISBIS with ECOG-PS (Eastern Cooperative Oncology Group - Performance Status), disease burden, sex, and NLR (neutrophil-to-lymphocyte ratio) demonstrated strong discrimination and validated accuracy.Conclusions A systemic immune-suppressive profile identifies patients with poor outcomes to ICIs. ISBIS integrates critical immune and inflammatory signals into a clinically applicable tool, supporting personalized immunotherapy strategies in advanced NSCLC.
A blood-based immune-suppressive index stratifies immunotherapy outcomes in advanced NSCLC
Lalli, Luca;Rossi, Giovanni;Novello, Silvia;Passiglia, Francesco
2026-01-01
Abstract
Background Immune checkpoint inhibitors (ICIs) provide durable benefit for a subset of patients with advanced non-small cell lung cancer (NSCLC), however predictive biomarkers remain limited. Peripheral blood offers accessible immune and inflammatory signals that may reflect the onset of systemic mechanisms of resistance. This study aimed to identify circulating immune features associated with clinical outcome and to develop a clinically applicable blood-based score for risk stratification in patients receiving ICIs.Methods Two independent real-world cohorts of advanced NSCLC patients treated with anti-PD-1 therapy were analyzed. Plasma cytokines and chemokines, soluble immune checkpoint molecules and blood cell counts were measured before and during ICI-therapy. Baseline biomarkers associated with progression-free survival (PFS) and overall survival (OS) were incorporated into an Immune-Suppressive Blood Index Score (ISBIS). The ISBIS discriminative performance was first determined in the discovery cohort (n=57) and then validated in an independent cohort (n=56), and nomogram integrating ISBIS with clinical variables was generated.Results ISBIS score predicts poor outcome to be associated with an immunosuppressive blood profile composed of baseline IL-6, IL-8, CCL2, CXCL10, neutrophils, PLR, IFN-gamma and lymphocytes. On-treatment increase in CXCL10, neutrophils, and NLR, as well as decreases in lymphocytes and soluble PD-L2, were associated with early disease progression. ISBIS stratified patients into three risk groups with significantly different survival in both cohorts and remained independently associated to OS. A nomogram combining ISBIS with ECOG-PS (Eastern Cooperative Oncology Group - Performance Status), disease burden, sex, and NLR (neutrophil-to-lymphocyte ratio) demonstrated strong discrimination and validated accuracy.Conclusions A systemic immune-suppressive profile identifies patients with poor outcomes to ICIs. ISBIS integrates critical immune and inflammatory signals into a clinically applicable tool, supporting personalized immunotherapy strategies in advanced NSCLC.
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