Immunosuppressive CD14+HLA-DRlo/neg monocytes are elevated in pancreatic cancer and "primed" by tumor-derived exosomes
Immunosuppressive CD14+HLA-DRlo/neg monocytes are elevated in pancreatic cancer and "primed" by tumor-derived exosomes
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DOI：
10.1080/2162402x.2016.1252013
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发表时间：
2017-01-01
期刊：
影响因子：
7.2
通讯作者：
Mukhopadhyay, Debabrata
中科院分区：
文献类型：
--
作者：
Javeed, Naureen;Gustafson, Michael P.;Mukhopadhyay, Debabrata
治疗胰腺癌的免疫策略提供了新的治疗方法来改善患者的预后。了解胰腺癌患者免疫系统的变化可能会导致该疾病免疫疗法的进步。我们使用流式细胞术分析了胰腺癌患者 (n = 22) 和年龄匹配的对照 (n = 20) 的外周血白细胞。胰腺癌患者的免疫分析发现了各种免疫细胞群的表型变化，包括免疫抑制性单核细胞群 (CD14(+)HLA-DRlo/neg)，这些细胞群在这些患者中有所增加。胰腺癌患者外周血CD14(+)单核细胞水平与CD14(+)HLA-DRlo/neg单核细胞水平存在相关性。单核细胞的 HLA-DR 下调被证明是通过胰腺癌衍生的外泌体与单核细胞的相互作用而发生的。在体外模型中，来自患者异种移植细胞系和患者血浆的外泌体降低了 CD14(+) 单核细胞上的 HLA-DR 表达。此外，肿瘤来源的外泌体通过改变 STAT3 信号传导、诱导精氨酸酶表达和活性氧在单核细胞中引起免疫抑制。这些发现为胰腺癌免疫抑制的控制机制提供了新的见解。了解单核细胞-外泌体相互作用可能会导致针对这种疾病的新型免疫疗法。
Immunological strategies to treat pancreatic cancer offer new therapeutic approaches to improve patient outcomes. Understanding alterations in the immune systems of pancreatic cancer patients will likely lead to advances in immunotherapy for the disease. We profiled peripheral blood leukocytes from pancreatic cancer patients (n = 22) and age-matched controls (n = 20) using flow cytometry. Immune profiling of pancreatic cancer patients identified phenotypic changes in various immune cell populations, including a population of immunosuppressive monocytes (CD14(+)HLA-DRlo/neg), which were shown to be increased in these patients. There was a correlation between the levels of CD14(+) monocytes and the levels of CD14(+)HLA-DRlo/neg monocytes in peripheral blood from pancreatic cancer patients. HLA-DR downregulation of monocytes was shown to occur through pancreatic cancer-derived exosome interactions with monocytes. In an in vitro model, exosomes from patient-derived xenograft cell lines and patient plasma decreased HLA-DR expression on CD14(+) monocytes. Additionally, tumor-derived exosomes caused immune suppression in monocytes through altered STAT3 signaling, induction of arginase expression, and reactive oxygen species. These findings provide novel insights into the mechanisms that govern immunosuppression in pancreatic cancer. Understanding monocyte-exosome interactions could lead to novel immunotherapies for this disease.