Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland.
Institute of Molecular Life Sciences, University of Zurich, Zurich, Switzerland.
Nat Med. 2018 Feb;24(2):144-153. doi: 10.1038/nm.4466. Epub 2018 Jan 8.
Immune-checkpoint blockade has revolutionized cancer therapy. In particular, inhibition of programmed cell death protein 1 (PD-1) has been found to be effective for the treatment of metastatic melanoma and other cancers. Despite a dramatic increase in progression-free survival, a large proportion of patients do not show durable responses. Therefore, predictive biomarkers of a clinical response are urgently needed. Here we used high-dimensional single-cell mass cytometry and a bioinformatics pipeline for the in-depth characterization of the immune cell subsets in the peripheral blood of patients with stage IV melanoma before and after 12 weeks of anti-PD-1 immunotherapy. During therapy, we observed a clear response to immunotherapy in the T cell compartment. However, before commencing therapy, a strong predictor of progression-free and overall survival in response to anti-PD-1 immunotherapy was the frequency of CD14CD16HLA-DR monocytes. We confirmed this by conventional flow cytometry in an independent, blinded validation cohort, and we propose that the frequency of monocytes in PBMCs may serve in clinical decision support.
免疫检查点阻断已彻底改变了癌症治疗。特别是程序性细胞死亡蛋白 1（PD-1）的抑制已被发现对转移性黑色素瘤和其他癌症的治疗有效。尽管无进展生存期显著延长，但很大一部分患者没有持久反应。因此，急需预测临床反应的生物标志物。在这里，我们使用高维单细胞质谱流式细胞术和生物信息学分析流程，对接受抗 PD-1 免疫治疗的 IV 期黑色素瘤患者外周血中的免疫细胞亚群进行了深入分析。在治疗过程中，我们观察到 T 细胞区室对免疫治疗有明显反应。然而，在开始治疗之前，对 PD-1 免疫治疗的无进展和总生存期的一个强有力的预测因子是 CD14^+CD16^+HLA-DR 单核细胞的频率。我们在一个独立的、盲法验证队列中通过常规流式细胞术进行了验证，并提出 PBMC 中单核细胞的频率可用于临床决策支持。
