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High Circulating IL-6/IL-8 Is Associated with Intratumoral Myeloid Contexture and Poor Outcomes in Patients with
Lucia Carril-Ajuria1,2, Ronan Flippot1,2, Marie Naigeon2,3
1Department of Medical Oncology, Gustave Roussy, Paris-Saclay University, Villejuif, 94805, France.
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.
Insights
High baseline levels of IL-6, IL-8, and VEGF predict worse outcomes in advanced clear cell renal cell carcinoma (aRCC) treated with nivolumab. These biomarkers correlate with myeloid tumor characteristics, aiding patient selection for future trials.
Area of Science:
- Oncology
- Immunotherapy
- Biomarker Discovery
Background:
- Advanced clear cell renal cell carcinoma (aRCC) remains a challenge, necessitating novel therapeutic strategies.
- Nivolumab has shown efficacy, but patient selection is crucial for optimal outcomes.
- Translational research is vital for understanding treatment response and identifying predictive biomarkers.
Purpose of the Study:
- To assess circulating biomarkers in a real-world population of pretreated aRCC patients receiving nivolumab.
- To investigate the association of baseline soluble factors with overall survival (OS) and intratumoral immune contexture.
- To identify predictive biomarkers for nivolumab efficacy in aRCC.
Main Methods:
- Prospective collection of baseline blood samples from 353 aRCC patients in the NIVOREN trial.
- Biomarker discovery in a cohort of 80 patients (responders vs. progressive disease) assessing 14 soluble factors.
- Validation of candidate biomarkers in the remaining 273 patients using RNA sequencing for gene expression signatures.
Main Results:
- Elevated baseline IL-6, IL-8, and VEGF were significantly associated with worse OS in both discovery and validation sets.
- Higher IL-6 and IL-8 levels correlated with a myeloid gene expression signature in tumor tissue.
- Hazard ratios for OS were 3.17 for IL-6, 2.11 for IL-8, and 1.36 for VEGF.
Conclusions:
- Circulating IL-6, IL-8, and VEGF are adverse prognostic biomarkers in nivolumab-treated aRCC patients.
- IL-6 and IL-8 demonstrated the strongest association with outcomes and myeloid immune contexture.
- These findings can guide patient selection for future clinical trials investigating nivolumab in aRCC.
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