Peripheral PD-1+CD56+ T-cell frequencies correlate with outcome in stage IV melanoma under PD-1 blockade

Immune checkpoint blockade with anti-PD-1 antibodies is showing great promise for patients with metastatic melanoma and other malignancies, but despite good responses by some patients who achieve partial or complete regression, many others still do not respond. Here, we sought peripheral blood T-cell biomarker candidates predicting treatment outcome in 75 stage IV melanoma patients treated with anti-PD-1 antibodies. We investigated associations with clinical response, progression-free survival (PFS) and overall survival (OS). Univariate analysis of potential biological confounders and known biomarkers, and a multivariate model, was used to determine statistical independence of associations between candidate biomarkers and clinical outcomes. We found that a lower than median frequency of peripheral PD-1+CD56+ T-cells was associated with longer OS (p = 0.004), PFS (p = 0.041) and superior clinical benefit (p = 0.009). However, neither frequencies of CD56-CD4+ nor CD56-CD8+ T-cells, nor of the PD-1+ fraction within the CD4 or CD8 subsets was associated with clinical outcome. In a multivariate model with known confounders and biomarkers only the M-category (HR, 3.11; p = 0.007) and the frequency of PD-1+CD56+ T-cells (HR, 2.39; p = 0.028) were identified as independent predictive factors for clinical outcome under PD-1 blockade. Thus, a lower than median frequency of peripheral blood PD-1+CD56+ T-cells prior to starting anti-PD-1 checkpoint blockade is associated with superior clinical response, longer PFS and OS of stage IV melanoma patients.针对转移性黑色素瘤及其他恶性肿瘤患者，抗PD-1抗体介导的免疫检查点阻断疗法已展现出良好的应用前景，但尽管部分患者可获得部分缓解或完全缓解，仍有多数患者无法从中获益。本研究旨在筛选可预测75例接受抗PD-1抗体治疗的IV期黑色素瘤患者治疗结局的外周血T细胞候选生物标志物，并探究其与临床应答、无进展生存期（PFS）及总生存期（OS）的关联。研究通过对潜在生物学混杂因素及已知生物标志物开展单因素分析，并构建多因素模型，以明确候选生物标志物与临床结局之间关联的统计学独立性。结果显示，外周血PD-1+CD56+ T细胞频率低于中位数者，其总生存期（p = 0.004）、无进展生存期（p = 0.041）及临床获益率（p = 0.009）均更优。然而，CD56阴性CD4+ T细胞、CD56阴性CD8+ T细胞的频率，以及CD4或CD8亚群内PD-1阳性组分的频率，均与临床结局无显著关联。在纳入已知混杂因素与生物标志物的多因素模型中，仅M分期（风险比HR, 3.11; p = 0.007）与PD-1+CD56+ T细胞频率（HR, 2.39; p = 0.028）被确定为PD-1阻断治疗下临床结局的独立预测因素。综上，启动抗PD-1免疫检查点阻断治疗前，外周血PD-1+CD56+ T细胞频率低于中位数的IV期黑色素瘤患者，可获得更优的临床应答、更长的无进展生存期与总生存期。