Depletion of CLL-associated patrolling monocytes and macrophages controls disease development and repairs immune dysfunction in vivo
Depletion of CLL-associated patrolling monocytes and macrophages controls disease development and repairs immune dysfunction in vivo
复制标题
DOI：
10.1038/leu.2015.305
复制
发表时间：
2016-03-01
期刊：
影响因子：
11.4
通讯作者：
Seiffert, M.
中科院分区：
文献类型：
--
作者：
Hanna, B. S.;McClanahan, F.;Seiffert, M.
慢性淋巴细胞白血病（CLL）的特征是细胞凋亡抵抗和免疫系统功能障碍。以前的报告表明，髓样细胞在介导这些缺陷中的潜在作用。然而，CLL相关骨髓细胞的组成和功能尚未在体内进行彻底研究。使用E mu-TCL 1小鼠模型，我们观察到随着CLL的发展，髓样细胞群严重偏斜。单核细胞和M2样巨噬细胞浸润白血病小鼠腹腔。单核细胞也以CCR 2依赖的方式在脾脏中积累，并且严重偏向Ly 6C（低）巡逻或非经典表型。此外，脾脏中MHC-IIhi树突状细胞和巨噬细胞的百分比显著下降。CLL相关单核细胞的基因表达谱显示异常高的PD-L1表达和多种炎症和免疫抑制细胞因子如白细胞介素-10、肿瘤坏死因子-α和CXCL 9的分泌。使用脂质体氯膦酸盐的体内骨髓细胞耗竭导致CLL发展的显著控制，伴随着先天免疫细胞表型的显著修复和全身性炎症的部分消退。此外，修复了CLL相关的T细胞向抗原经历表型的倾斜。目前的数据表明，针对非恶性骨髓细胞可能作为一种新的免疫治疗策略CLL。
Chronic lymphocytic leukemia (CLL) is characterized by apoptosis resistance and a dysfunctional immune system. Previous reports suggested a potential role of myeloid cells in mediating these defects. However, the composition and function of CLL-associated myeloid cells have not been thoroughly investigated in vivo. Using the E mu-TCL1 mouse model, we observed severe skewing of myeloid cell populations with CLL development. Monocytes and M2-like macrophages infiltrated the peritoneal cavity of leukemic mice. Monocytes also accumulated in the spleen in a CCR2-dependent manner, and were severely skewed toward Ly6C(low) patrolling or nonclassical phenotype. In addition, the percentage of MHC-IIhi dendritic cells and macrophages significantly dropped in the spleen. Gene expression profiling of CLL-associated monocytes revealed aberrantly high PD-L1 expression and secretion of multiple inflammatory and immunosuppressive cytokines like interleukin-10, tumor necrosis factor-alpha and CXCL9. In vivo myeloid cell depletion using liposomal Clodronate resulted in a significant control of CLL development accompanied by a pronounced repair of innate immune cell phenotypes and a partial resolution of systemic inflammation. In addition, CLL-associated skewing of T cells toward antigen-experienced phenotypes was repaired. The presented data suggest that targeting nonmalignant myeloid cells might serve as a novel immunotherapeutical strategy for CLL.