Host-derived immunometabolic biomarkers identify prognostic profiles under immunotherapy in advanced NSCLC: the SARC-LUNG study

Abstract

Immune checkpoint inhibitors (ICIs) improve outcomes in advanced non-small cell lung cancer (NSCLC), but predictive biomarkers remain limited. Host-derived immunometabolic factors may modulate response to ICIs. In the prospective SARC-LUNG study, 40 patients with advanced NSCLC treated with first-line ICIs (± chemotherapy) underwent longitudinal assessment of circulating biomarkers (sRAGE, FGF21, GDF15, cPLIN2) and computed tomography (CT)-derived body composition parameters. Associations with progression-free survival (PFS) and overall survival (OS) were analyzed using Cox regression models. FGF21 and sRAGE were further assessed in an independent cohort of 76 patients. In silico transcriptomic analyses explored associations between biomarker-related genes and immune microenvironment signatures. High baseline sRAGE levels were associated with longer PFS and OS in the exploratory cohort, whereas increasing sRAGE levels during treatment correlated with response. Elevated FGF21 levels were associated with worse OS (HR 1.11, p  = 0.026) and inversely correlated with lean mass. In the independent cohort, higher FGF21 levels remained independently associated with shorter PFS and OS, whereas sRAGE was not associated with survival. PLIN2 and sRAGE tumor gene expression were associated with immune-inflammatory phenotypes, while FGF21 and GDF15 with immune-desert phenotypes. Host-derived immunometabolic biomarkers are associated with clinical outcomes and distinct immune microenvironment profiles in advanced NSCLC treated with ICIs.