Background: Immune checkpoint inhibition has revolutionized melanoma therapy, but many patients show primary or secondary resistance. Biomarkers are, therefore, urgently required to predict response prior to the initiation of therapy and to monitor disease progression. Methods: In this prospective study, we analyzed the serum C-C motif chemokine ligand 20 (CCL20) concentration using an enzyme-linked immunosorbent assay. Blood was obtained at baseline before the initiation of immunotherapy with anti-PD-1 monotherapy or Nivolumab and Ipilimumab in advanced melanoma patients (stages III and IV) enrolled at the University Medical Center Hamburg-Eppendorf. The CCL20 levels were correlated with clinico-pathological parameters and disease-related outcomes. Results: An increased C-C motif chemokine ligand 20 (CCL20) concentration (≥0.34 pg/mL) at baseline was associated with a significantly impaired progression-free survival (PFS) in the high-CCL20 group (3 months (95% CI: 2–6 months) vs. 11 months (95% CI: 6–26 months)) (p= 0.0033) and could be identified as an independent negative prognostic factor for PFS in univariate (Hazard Ratio (HR): 1.98, 95% CI 1.25–3.12,p= 0.004) and multivariate (HR: 1.99, 95% CI 1.21–3.29,p= 0.007) Cox regression analysis, which was associated with a higher risk than S100 (HR: 1.74). Moreover, high CCL20 levels were associated with impaired overall survival (median OS not reached for low-CCL20 group,p= 0.042) with an HR of 1.85 (95% CI 1.02–3.37,p= 0.043) in univariate analysis similar to the established prognostic marker S100 (HR: 1.99, 95% CI: 1.02–3.88,p= 0.043). Conclusions: CCL20 may represent a novel blood-based biomarker for the prediction of resistance to immunotherapy that can be used in combination with established strong clinical predictors (e.g., ECOG performance score) and laboratory markers (e.g., S100) in advanced melanoma patients. Future prospective randomized trials are needed to establish CCL20 as a liquid biopsy-based biomarker in advanced melanoma.
背景：免疫检查点抑制剂已彻底改变黑色素瘤的治疗策略，但许多患者仍表现出原发性或继发性耐药。因此，亟需在治疗开始前预测疗效及监测疾病进展的生物标志物。方法：本前瞻性研究采用酶联免疫吸附法检测血清C-C基序趋化因子配体20（CCL20）浓度。研究对象为汉堡-埃彭多夫大学医学中心收治的晚期黑色素瘤患者（III期和IV期），在开始抗PD-1单药或纳武利尤单抗联合伊匹木单抗免疫治疗前采集基线血液样本。将CCL20水平与临床病理参数及疾病相关结局进行相关性分析。结果：基线期CCL20浓度升高（≥0.34 pg/mL）与高CCL20组显著缩短的无进展生存期相关（3个月（95% CI：2-6个月）对比11个月（95% CI：6-26个月））（p=0.0033）。单因素（风险比（HR）：1.98，95% CI 1.25-3.12，p=0.004）和多因素（HR：1.99，95% CI 1.21-3.29，p=0.007）Cox回归分析均证实CCL20是PFS的独立负向预后因素，其风险值高于S100（HR：1.74）。此外，高CCL20水平与总生存期缩短相关（低CCL20组中位OS未达到，p=0.042），单因素分析显示HR为1.85（95% CI 1.02-3.37，p=0.043），与已确立的预后标志物S100具有相似预测效能（HR：1.99，95% CI：1.02-3.88，p=0.043）。结论：CCL20可能成为预测晚期黑色素瘤患者免疫治疗耐药的新型血液生物标志物，可与现有强临床预测因子（如ECOG体能评分）及实验室标志物（如S100）联合应用。未来需开展前瞻性随机试验以确立CCL20作为晚期黑色素瘤液体活检生物标志物的临床价值。
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