Buschow Sonja I, Ramazzotti Matteo, Reinieren-Beeren Inge M J, Heinzerling Lucie M, Westdorp Harm, Stefanini Irene, Beltrame Luca, Hato Stanleyson V, Ellebaek Eva, Gross Stefanie, Nguyen Van Anh, Weinlich Georg, Ragoussis Jiannis, Baban Dilair, Schuler-Thurner Beatrice, Svane Inge M, Romani Nikolaus, Austyn Jonathan M, De Vries I Jolanda M, Schuler Gerold, Cavalieri Duccio, Figdor Carl G
Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
Department of Gastroenterology and Hepatology, Erasmus University Medical Center (Erasmus MC), Rotterdam, The Netherlands.
Oncotarget. 2017 Jun 27;8(40):67439-67456. doi: 10.18632/oncotarget.18698. eCollection 2017 Sep 15.
Immunotherapy for metastatic melanoma offers great promise but, to date, only a subset of patients have responded. There is an urgent need to identify ways of allocating patients to the most beneficial therapy, to increase survival and decrease therapy-associated morbidity and costs. Blood-based biomarkers are of particular interest because of their straightforward implementation in routine clinical care. We sought to identify markers for dendritic cell (DC) vaccine-based immunotherapy against metastatic melanoma through gene expression analysis of peripheral blood mononuclear cells. A large-scale microarray analysis of 74 samples from two treatment centers, taken directly after the first round of DC vaccination, was performed. We found that phosphatidylethanolamine binding protein 1 (/Raf Kinase inhibitory protein (RKIP) expression can be used to identify a significant proportion of patients who performed poorly after DC vaccination. This result was validated by q-PCR analysis on blood samples from a second cohort of 95 patients treated with DC vaccination in four different centers. We conclude that low expression correlates with poor overall survival after DC vaccination. Intriguingly, this was only the case for expression of after, but not prior to, DC vaccination. Moreover, the change in expression upon vaccination correlated well with survival. Further analyses revealed that expression positively correlated with genes involved in T cell responses but inversely correlated with genes associated with myeloid cells and aberrant inflammation including , and . Concordantly, PEBP1 inversely correlated with the myeloid/lymphoid-ratio and was suppressed in patients suffering from chronic inflammatory disease.
转移性黑色素瘤的免疫疗法前景广阔，但迄今为止，只有一部分患者有反应。迫切需要确定将患者分配到最有益治疗方法的方式，以提高生存率并降低治疗相关的发病率和成本。基于血液的生物标志物因其在常规临床护理中的直接应用而备受关注。我们试图通过对外周血单核细胞进行基因表达分析，来确定基于树突状细胞（DC）疫苗的转移性黑色素瘤免疫疗法的标志物。对来自两个治疗中心的74个样本进行了大规模微阵列分析，这些样本是在第一轮DC疫苗接种后直接采集的。我们发现磷脂酰乙醇胺结合蛋白1（/Raf激酶抑制蛋白（RKIP）的表达可用于识别很大一部分在DC疫苗接种后表现不佳的患者。这一结果在对来自四个不同中心接受DC疫苗接种的95名患者的第二个队列的血样进行q-PCR分析时得到了验证。我们得出结论，低表达与DC疫苗接种后的总体生存率低相关。有趣的是，只有在DC疫苗接种后而非接种前的表达才是这种情况。此外，接种后表达的变化与生存率密切相关。进一步分析表明，表达与参与T细胞反应的基因呈正相关，但与与髓样细胞和异常炎症相关的基因呈负相关，包括和。一致地，PEBP1与髓样/淋巴细胞比率呈负相关，并且在患有慢性炎症性疾病的患者中受到抑制。
