Department of Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA.
Clin Cancer Res. 2013 Jul 1;19(13):3404-15. doi: 10.1158/1078-0432.CCR-13-0525. Epub 2013 May 7.
To determine the role of the CCL2/CCR2 axis and inflammatory monocytes (CCR2(+)/CD14(+)) as immunotherapeutic targets in the treatment of pancreatic cancer.
Survival analysis was conducted to determine if the prevalence of preoperative blood monocytes correlates with survival in patients with pancreatic cancer following tumor resection. Inflammatory monocyte prevalence in the blood and bone marrow of patients with pancreatic cancer and controls was compared. The immunosuppressive properties of inflammatory monocytes and macrophages in the blood and tumors, respectively, of patients with pancreatic cancer were assessed. CCL2 expression by human pancreatic cancer tumors was compared with normal pancreas. A novel CCR2 inhibitor (PF-04136309) was tested in an orthotopic model of murine pancreatic cancer.
Monocyte prevalence in the peripheral blood correlates inversely with survival, and low monocyte prevalence is an independent predictor of increased survival in patients with pancreatic cancer with resected tumors. Inflammatory monocytes are increased in the blood and decreased in the bone marrow of patients with pancreatic cancer compared with controls. An increased ratio of inflammatory monocytes in the blood versus the bone marrow is a novel predictor of decreased patient survival following tumor resection. Human pancreatic cancer produces CCL2, and immunosuppressive CCR2(+) macrophages infiltrate these tumors. Patients with tumors that exhibit high CCL2 expression/low CD8 T-cell infiltrate have significantly decreased survival. In mice, CCR2 blockade depletes inflammatory monocytes and macrophages from the primary tumor and premetastatic liver resulting in enhanced antitumor immunity, decreased tumor growth, and reduced metastasis.
Inflammatory monocyte recruitment is critical to pancreatic cancer progression, and targeting CCR2 may be an effective immunotherapeutic strategy in this disease.
确定 CCL2/CCR2 轴和炎症性单核细胞（CCR2(+)/CD14(+））作为治疗胰腺癌的免疫治疗靶点的作用。
进行生存分析以确定术前血单核细胞的流行率是否与胰腺癌患者在肿瘤切除后的生存相关。比较了胰腺癌患者和对照组的血液和骨髓中炎症性单核细胞的流行率。评估了血液中炎症性单核细胞和巨噬细胞以及肿瘤中分别对胰腺癌患者的免疫抑制特性。将人胰腺癌细胞肿瘤的 CCL2 表达与正常胰腺进行了比较。在小鼠胰腺癌的原位模型中测试了一种新型 CCR2 抑制剂（PF-04136309）。
外周血单核细胞的流行率与生存呈负相关，低单核细胞流行率是切除肿瘤的胰腺癌患者生存时间延长的独立预测因素。与对照组相比，胰腺癌患者的血液中炎症性单核细胞增加，骨髓中炎症性单核细胞减少。血液中炎症性单核细胞与骨髓中炎症性单核细胞的比值增加是肿瘤切除后患者生存时间减少的新预测因素。人胰腺癌细胞产生 CCL2，并且免疫抑制性 CCR2(+)巨噬细胞浸润这些肿瘤。表现出高 CCL2 表达/低 CD8 T 细胞浸润的肿瘤患者的生存时间明显缩短。在小鼠中，CCR2 阻断从原发性肿瘤和前转移肝脏中耗尽炎症性单核细胞和巨噬细胞，从而增强了抗肿瘤免疫，减少了肿瘤生长并降低了转移。
炎症性单核细胞募集对胰腺癌的进展至关重要，靶向 CCR2 可能是该疾病有效的免疫治疗策略。
