PAtient Lipidome As biomarker of Cancer immunothErapy (PALACE): preliminary relevant results

Background: The PALACE study investigated whether lipid metabolism, systemic inflammation, immune system and nutritional status could predict response to immune checkpoint inhibitors (ICIs) in advanced non-small cell lung cancer (NSCLC). Methods: 23 patients with stage IIIC/IV NSCLC treated with ICIs ± chemotherapy were enrolled. Clinical, nutritional, body composition and several circulating biomarkers were evaluated at baseline (V0) and at V1 (~9 weeks after V0). Gene expression analyses of FFPE tumor samples were also performed. Data were correlated with clinical outcomes using standard statistical methods and with response to ICIs through AI-based approaches. Results: Immune-related adverse events were associated with a trend toward improved progression-free survival (PFS) and were more frequent in responders (Rs) (p=0.078; p<0.001). Hypercholesterolemia and statin use also predominated among Rs (p=0.015). At V1, Rs had higher HDL levels, whereas non-responders (NRs) had higher LDL and triglyceride levels (p<0.001). Regarding body composition, at V0 Rs were significantly associated with higher fat mass/height, whereas NRs were characterized by lower fat-free mass/height (kg/m) (p<0.001). Circulating fatty acids assessment showed that higher linoleic acid at V1 correlated with a trend toward shorter PFS (p=0.080), whereas higher arachidonic acid showed a trend toward improved overall survival (OS) at V0 and V1 (p=0.061; p=0.087) and higher palmitic acid at V0 was associated with shorter OS (p=0.065). Among cytokines and adipokines, higher IL-10 at V1 was associated with shorter PFS (p=0.036), while IFN-γ at V0 and V1 correlated with trends toward reduced OS (p=0.075; p=0.085), and Rs tended to have higher adiponectin at V1 (p=0.065). At the molecular level, CD274 positively correlated with ABCA1 (p<0.001), whereas PDCD1 negatively correlated with PRKAA1, INSIG1, and STARD3 (p=0.003; p=0.005; p=0.010). Moreover, Rs showed higher APOL1 expression, with a trend toward statistical significance (p=0.081). Conclusions: With a relevant contribution from AI-based approaches, PALACE identified a preliminary immunometabolic signature associated with ICI outcomes in advanced NSCLC. These findings support the clinical potential of circulating lipidomic and immune markers for early patient stratification, although validation in larger cohorts is warranted.