转移性葡萄膜黑色素瘤患者趋化因子分析提示 CCL21 信号在联合表观遗传治疗和检查点免疫治疗中的作用。

PURPOSE: Patients with metastatic uveal melanoma have limited therapeutic options and high mortality rate so new treatment options are needed. PATIENTS AND METHODS: We previously reported that patients treated with the PD-1 inhibitor pembrolizumab and the histone deacetylase inhibitor entinostat in the PEMDAC trial, experienced clinical benefits if their tumor originated from iris or was wildtype for tumor suppressor gene. Here we present the 2-year follow-up of the patients in the PEMDAC trial and identify additional factors that correlate with response or survival. RESULTS: Durable responses were observed in 4 patients, with additional 8 patients exhibiting a stable disease. The median overall survival was 13.7 months. Grade 3 adverse events were reported in 62% of the patients, but they were all manageable. No fatal toxicity was observed. Activity of thymidine kinase 1 in plasma was higher in patients with stable disease or who progressed on treatment, compared with those with partial response. Chemokines and cytokines were analyzed in plasma. Three chemokines were significantly different when comparing patients with and without response. One of the factors, CCL21, was higher in the plasma of responding patients before treatment initiation but decreased in the same patients upon treatment. In tumors, CCL21 was expressed in areas resembling tertiary lymphoid structures (TLS). High plasma levels of CCL21 and presence of TLS-like regions in the tumor correlated with longer survival. CONCLUSIONS: This study provides insight into durable responses in the PEMDAC trial, and describes dynamic changes of chemokines and cytokines in the blood of these patients. SIGNIFICANCE: The most significant finding from the 2-year follow-up study of the PEMDAC trial was that high CCL21 levels in blood was associated with response and survival. CCL21 was also expressed in TLS-like regions and presence of these regions was associated with longer survival. These analyses of soluble and tumor markers can inform on predictive biomarkers needing validation and become hypothesis generating for experimental research.

目的：转移性葡萄膜黑色素瘤患者的治疗选择有限，死亡率高，因此需要新的治疗选择。

患者和方法：我们之前报道过，在 PEMDAC 试验中接受 PD-1 抑制剂 pembrolizumab 和组蛋白去乙酰化酶抑制剂 entinostat 治疗的患者，如果肿瘤起源于虹膜或肿瘤抑制基因野生型，则会有临床获益。在这里，我们呈现了 PEMDAC 试验中患者的 2 年随访结果，并确定了与反应或生存相关的其他因素。

结果：4 名患者出现持久反应，另外 8 名患者出现稳定疾病。中位总生存期为 13.7 个月。62%的患者报告有 3 级不良事件，但均可控。未观察到致命毒性。与部分缓解的患者相比，在治疗进展或稳定的患者中，血浆中的胸苷激酶 1 活性更高。分析了血浆中的趋化因子和细胞因子。在比较有反应和无反应的患者时，有 3 种趋化因子有显著差异。其中一种趋化因子 CCL21 在开始治疗前的反应患者的血浆中较高，但在同一患者治疗后降低。在肿瘤中，CCL21 在类似于三级淋巴样结构（TLS）的区域表达。血浆中 CCL21 水平较高和肿瘤中存在 TLS 样区域与更长的生存时间相关。

结论：本研究为 PEMDAC 试验中的持久反应提供了深入了解，并描述了这些患者血液中趋化因子和细胞因子的动态变化。

意义：从 PEMDAC 试验的 2 年随访研究中得出的最重要发现是，血液中高 CCL21 水平与反应和生存相关。CCL21 也在 TLS 样区域表达，这些区域的存在与更长的生存时间相关。这些对可溶性和肿瘤标志物的分析可以为需要验证的预测生物标志物提供信息，并为实验研究提供假设生成。