IUC26693-91 Cholesterol homeostasis and immune-inflammatory profiles in patients with mRCC receiving immunotherapy

Abstract Background Cholesterol metabolism may modulate antitumor immunity, influencing response to immune-checkpoint inhibitors (ICIs). We evaluated cholesterol transport-related biomarkers, KIM-1, and inflammatory mediators in metastatic renal cell carcinoma (mRCC) patients treated with first-line ICI-based regimens, to characterize the immune–metabolic profiles. Methods LINCHOLM is a prospective, multicentre, observational study. Patients with mRCC receiving ICI-based combinations underwent blood collection at baseline, week 6 and progression. ABCA1- and ABCG1-mediated cholesterol efflux (CE), lipid fractions, and inflammatory mediators were assessed. Primary objective was to investigate associations between baseline cholesterol transporters and inflammatory mediators, and progression-free survival (PFS). Results 33 patients were included, 84.8% had ECOG PS 0-1. Across worsening IMDC risk groups Apo-A1, total cholesterol, HDL and LDL decreased (all p≤0.03), whereas KIM-1, IL-6 and Apo-E increased (all p≤0.02). High ABCG1-mediated CE correlated with higher levels of ApoE and IL-1β (all p≤0.04). High KIM-1 was associated with poorer ECOG PS, synchronous metastatic disease, and higher NLR, IL-4, IL-6, and IL-10 (all p≤0.04), Figure 1. High baseline ABCG1-mediated CE, KIM-1, ApoE, NLR, and inflammatory cytokines (IL-4, IL-6, IFN-γ, IL-10, IL-1β, IL-2, and TNF-α) correlated with shorter PFS, Table 1. Only ABCG1 remained independently associated with worse PFS at multivariable analysis (HR 10.61, 95%CI 2.35–47.97; p = 0.002), although estimates were limited by small sample size. Conclusions ABCG1-mediated CE may serve as a prognostic biomarker in mRCC patients receiving first-line ICI-based therapies. The interplay among cholesterol metabolism, KIM-1, and inflammatory mediators suggests a biological profile influencing outcomes and warrants further validation. Acknowledgements Project funded by the European Union - NextGenerationEU, Mission 4 Component 1, Unique Project Code (CUP): D53D23013940006