Cholesterol transporters and immune-metabolic features in patients with metastatic renal cell carcinoma receiving immunotherapy combinations

BACKGROUND: Despite improved outcomes with immune checkpoint inhibitor (ICI) combinations in metastatic renal cell carcinoma (mRCC), reliable biologically-driven prognostic markers remain needed. The CHOMET study evaluated tumor ABCA1/ABCG1 expression and their association with systemic lipid parameters, nutritional status, nephrectomy status and survival outcomes. METHODS: CHOMET was a retrospective observational biomarker study including mRCC patients undergoing first-line ICI-combinations. Tumor ABCA1 and ABCG1 expressions were assessed by immunohistochemistry (IHC). Serum total cholesterol (TC), triglycerides (TG), and the Controlling Nutritional Status score (CONUT) were collected. Publicly available transcriptomic datasets were used for exploratory bulk RNA-seq, immune deconvolution, and single-cell analyses. RESULTS: Among 86 patients (46 with IHC), high ABCA1 and ABCG1 expression was associated with shorter overall survival (OS, p = 0.003 and p = 0.01) and progression-free survival (PFS, p = 0.05 and p = 0.08). A composite nephrectomy-cholesterol score and a lower CONUT score were both significantly associated with improved PFS and OS. Exploratory bulk RNA-seq analyses suggested that high ABCA1 expression correlated with features of an immunosuppressive microenvironment enriched in M2 macrophages and depleted of CD8+ T cells, whereas high ABCG1 expression correlated with increased regulatory T cells. Exploratory single-cell analyses from four patients showed ABCA1 and ABCG1 expression across tumor-associated macrophages and tumor cells, with donor-specific pathway enrichment patterns involving immune signaling and cholesterol metabolism-related transcriptional programs. CONCLUSIONS: ABCA1 and ABCG1 expression levels were associated with poorer outcomes in mRCC treated with ICI combinations and support a link between cholesterol transport programs and an immunosuppressive, metabolically reprogrammed tumor microenvironment.