ABSTRACT

In the era of immunotherapies there is an urgent need to implement the use of circulating biomarkers in clinical practice to facilitate personalized therapy and to predict treatment response. We conducted a prospective study to evaluate the usefulness of circulating exosomal-PD-L1 in melanoma patients’ follow-up. We studied the dynamics of exosomal-PD-L1 from 100 melanoma patients by using an enzyme-linked immunosorbent assay. We found that PD-L1 was secreted through exosomes by melanoma cells. Exosomes carrying PD-L1 had immunosuppressive properties since they were as efficient as the cancer cell from which they derive at inhibiting T-cell activation. In plasma from melanoma patients, the level of PD-L1 (n= 30, median 64.26 pg/mL) was significantly higher in exosomes compared to soluble PD-L1 (n= 30, 0.1 pg/mL). Furthermore, exosomal-PD-L1 was detected in all patients whereas only 67% of tumour biopsies were PD-L1 positive. Although baseline exosomal-PD-L1 levels were not associated with clinic-pathologic characteristics, their variations after the cures (ΔExoPD-L1) correlated with the tumour response to treatment. A ΔExoPD-L1 cut-off of> 100 was defined, yielding an 83% sensitivity, a 70% specificity, a 91% positive predictive value and 54% negative predictive values for disease progression. The use of the cut-off allowed stratification in two groups of patients statistically different concerning overall survival and progression-free survival. PD-L1 levels in circulating exosomes seem to be a more reliable marker than PD-L1 expression in tumour biopsies. Monitoring of circulating exosomal-PD-L1 may be useful to predict the tumour response to treatment and clinical outcome.

摘要

在免疫疗法时代，迫切需要在临床实践中使用循环生物标记物，以促进个性化治疗和预测治疗反应。我们进行了一项前瞻性研究，以评估循环外泌体PD-L1在黑色素瘤患者随访中的作用。我们使用酶联免疫吸附试验研究了来自100名黑色素瘤患者的外泌体PD-L1的动力学。我们发现PD-L1是黑色素瘤细胞通过外泌体分泌的。携带PD-L1的外泌体具有免疫抑制特性，因为它们与它们所衍生的癌细胞一样有效，可以抑制T细胞活化。在黑色素瘤患者的血浆中，外来体中的PD-L1水平（n = 30，中位值64.26 pg / mL）显着高于可溶性PD-L1（n = 30，0.1 pg / mL）。此外，在所有患者中均检测到外泌体PD-L1，而只有67％的肿瘤活检标本为PD-L1阳性。尽管基线外泌体PD-L1水平与临床病理特征无关，但治愈后的变化（ΔExoPD-L1）与肿瘤对治疗的反应相关。定义了> 100的ΔExoPD-L1临界值，得出疾病进展的敏感性为83％，特异性为70％，阳性预测值为91％，阴性预测值为54％。截止值的使用允许两组患者在总体生存和无进展生存方面存在统计学差异。循环外泌体中的PD-L1水平似乎比肿瘤活检中的PD-L1表达更可靠。