PDF(Pubmed)
Abstract：
The human dendritic cell (DC) family has recently been expanded by CD1c+CD14+CD163+ DCs, introduced as DC3s. DC3s are found in tumors and peripheral blood of cancer patients. Here, we report elevated frequencies of CD14+ cDC2s, which restore to normal frequencies after tumor resection, in non-small cell lung cancer patients. These CD14+ cDC2s phenotypically resemble DC3s and exhibit increased PD-L1, MERTK, IL-10, and IDO expression, consistent with inferior T cell activation ability compared with CD14- cDC2s. In melanoma patients undergoing CD1c+ DC vaccinations, increased CD1c+CD14+ DC frequencies correlate with reduced survival. We demonstrate conversion of CD5+/-CD1c+CD14- cDC2s to CD14+ cDC2s by tumor-associated factors, whereas monocytes failed to express CD1c under similar conditions. Targeted proteomics identified IL-6 and M-CSF as dominant drivers, and we show that IL-6R and CSF1R inhibition prevents tumor-induced CD14+ cDC2s. Together, this indicates cDC2s as direct pre-cursors of DC3-like CD1c+CD14+ DCs and provides insights into the importance and modulation of CD14+ DC3s in anti-tumor immune responses.
摘要：
人类树突状细胞（DC）家族最近通过CD1c+CD14+CD163+DCs扩展，作为DC3s引入。DC3s存在于肿瘤和癌症患者的外周血中。这里,我们报告了CD14+cDC2s的频率升高，肿瘤切除后恢复到正常频率，非小细胞肺癌患者。这些CD14+cDC2s表型类似于DC3s，并表现出增加的PD-L1，MERTK，IL-10和IDO表达，与CD14-cDC2s相比，T细胞活化能力较差。在接受CD1c+DC疫苗接种的黑色素瘤患者中，CD1c+CD14+DC频率增加与生存率降低相关.我们证明了肿瘤相关因子将CD5+/-CD1c+CD14-cDC2s转化为CD14+cDC2s，而单核细胞在相似条件下未能表达CD1c。靶向蛋白质组学将IL-6和M-CSF确定为显性驱动因子，我们显示IL-6R和CSF1R抑制可防止肿瘤诱导的CD14+cDC2s。一起,这表明cDC2s是DC3样CD1c+CD14+DCs的直接前体，并提供了对CD14+DC3s在抗肿瘤免疫反应中的重要性和调节的见解。
