30 Myeloid- Versus Effector-Driven Circulating Immune States Define Treatment-Specific Benefit in Metastatic Clear Cell Renal Cell Carcinoma

Abstract

Abstract Background Metastatic clear cell renal cell carcinoma (ccRCC) first-line treatment relies on immune checkpoint inhibitor (ICI)-based regimens, including either dual ICI or ICI plus antiangiogenic tyrosine kinase inhibitor (TKI). Despite substantial clinical progress, predictive biomarkers guiding regimen selection are lacking. Circulating biomarkers may provide a broader and more accessible overview of the tumor immune landscape compared with tissue-based biomarkers. Methods To assess whether circulating immune factors reflect tumor immunobiology and could guide regimen selection, we studied a prospective cohort of 27 patients with metastatic ccRCC initiating first-line combination immunotherapy (NCT04932525). Circulating immune subsets were characterized by single-cell transcriptomic profiling of peripheral blood mononuclear cells (PBMCs), while soluble factors were profiled with the Olink Target 96 Immuno-Oncology panel. Associations between immune features and treatment response were explored across therapeutic regimens (dual ICI vs ICI-TKI).c Results Transcriptomic profiling of circulating immune cells revealed distinct immune cell compositions associated with treatment response. Effector CD8+ T cells, NK populations, and non-classical monocytes (CD16+) were enriched in responders to dual ICI (all p < 0.001, χ² test). Conversely, classical inflammatory monocytes were strongly associated with resistance to dual ICI (p < 0.001, χ² test). These associations were not observed in the ICI-TKI subgroup. Integration with soluble factor data revealed that myeloid-driven inflammatory cytokines (IL6, IL8, CCL23) and hypoxia-related cytokines (PGF, HGF, VEGFA) were positively correlated with the abundance of classical monocytes (mean ρ = 0.66 and 0.65, respectively; both p < 0.01), while being inversely correlated with effector T-cell and NK cell populations. Notably, hypoxia-related cytokines were associated with response in the ICI-TKI subgroup (Wilcoxon p = 0.04), suggesting distinct immune-angiogenic dynamics across therapeutic arms. Conclusions Circulating soluble factors can capture systemic immune states with therapeutic relevance in ccRCC. A myeloid-skewed and hypoxia-driven immune landscape aligned with lack of benefit from dual ICI, yet tracked with clinical activity of ICI-TKI combinations. Conversely, an immune context enriched in effector T/NK features and non-classical monocytes was associated with improved outcomes under dual ICI. These findings highlight the potential of circulating multi-omic profiling to inform regimen selection and unravel distinct immunobiological determinants of response and resistance in metastatic ccRCC.