High Circulating IL-6/IL-8 Is Associated with Intratumoral Myeloid Contexture and Poor Outcomes in Patients with Advanced Renal Cell Carcinoma Treated with PD-1 Blockade

PURPOSE: The phase II NIVOREN GETUG-AFU 26 study assessed the safety and activity of nivolumab in a real-world population with pretreated advanced clear-cell renal cell carcinoma. A comprehensive translational research program was conducted, including blood- and tissue-based analyses. In this study, we assessed circulating factors at baseline, their association with intratumoral immune contexture, and outcomes. EXPERIMENTAL DESIGN: Baseline blood samples were prospectively collected from 353 patients included in the NIVOREN trial. A cohort of 80 patients, including 40 responders and 40 with primary progressive disease, was used for biomarker discovery, with 14 soluble factors (VEGF, vascular cell adhesion molecule-1, IL-6, IL-7, IL-8, IL-10, APRIL, B-cell activating factor, 4-1BB, B-cell attracting chemokine, stromal cell-derived factor-1, macrophage-derived chemokine, IFN-γ, and TNF-α) assessed for association with overall survival (OS; discovery set). Candidate biomarkers were subsequently assessed in the remaining 273 patients for association with outcomes (validation set). Gene expression signatures were assessed on baseline tissue samples using RNA sequencing. RESULTS: Five candidate biomarkers, IL-6, IL-7, IL-8, VEGF, and 4-1BB, were significantly associated with OS in the discovery set. We confirmed in the validation set a significant adverse association between OS and higher baseline levels of IL-6, IL-8, and VEGF, with respective HR of 3.17 [95% confidence interval (CI), 2.29-4.40], 2.11 (95% CI, 1.60-2.80), and 1.36 (95% CI, 1.04-1.79). Higher IL-6 and IL-8 levels were associated with an intratumor IMmotion Myeloid gene expression signature (P = 0.004 and P = 0.041, respectively). CONCLUSIONS: Elevated baseline circulating IL-6, IL-8, and VEGF are associated with worse outcomes in patients with nivolumab-treated advanced clear-cell renal cell carcinoma. Circulating IL-6 and IL-8 showed the strongest association with outcomes and correlated with a myeloid tissue contexture, providing guidance for patient selection in future trials.