Chen Sha-Yan, Yang Xiao, Feng Wen-Li, Liao Jin-Feng, Wang Li-Na, Feng Li, Lin Yong-Min, Ren Qian, Zheng Guo-Guang
State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020, China; and.
State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020, China; and Center for Stem Cell Medicine, Chinese Academy of Medical Sciences, Beijing 100730, China
J Immunol. 2015 Mar 15;194(6):2919-29. doi: 10.4049/jimmunol.1400451. Epub 2015 Feb 6.
Tumor-associated macrophages are widely studied in solid tumors. The distribution of macrophages in lymph node samples was found to be associated with the prognosis of lymphoma patients. However, the role of macrophages in leukemia and their functional and phenotypic characteristics in hematopoietic malignancies have not been defined. In this study, we examined the distribution and functional and phenotypic characteristics of macrophages in a Notch1-induced mouse model of T cell acute lymphoblastic leukemia (T-ALL). The distribution of macrophages in bone marrow (BM) and spleen, which are proposed as BM and spleen leukemia-associated macrophages (LAMs), were different during the development of leukemia. LAMs stimulated the proliferation of T-ALL cells and had higher migration activity. RNA-sequencing analysis revealed that gene expression profiles of BM and spleen LAMs showed considerable differences. RT-PCR analysis showed that LAMs expressed both M1- and M2-associated phenotypic genes, but they expressed much lower levels of TGF-β1, VEGF-A, and CSF-1 than did tumor-associated macrophages from B16 melanoma. Furthermore, spleen LAMs more potently stimulated the proliferation of T-ALL cells compared with BM LAMs. Moreover, LAMs could be subdivided into M1-like (CD206(-)) and M2-like (CD206(+)) groups. Both CD206(+) and CD206(-) LAMs stimulated the proliferation of T-ALL cells, although CD206(+) LAMs expressed higher levels of most M1- and M2-associated genes. These results suggested the functional and phenotypic characteristics of LAMs, which were modified by organ specific microenvironments. Our results broaden our knowledge about macrophages in malignant microenvironments from solid tumors to leukemia.
肿瘤相关巨噬细胞在实体瘤中得到了广泛研究。研究发现，淋巴结样本中巨噬细胞的分布与淋巴瘤患者的预后相关。然而，巨噬细胞在白血病中的作用及其在造血系统恶性肿瘤中的功能和表型特征尚未明确。在本研究中，我们在Notch1诱导的T细胞急性淋巴细胞白血病（T-ALL）小鼠模型中检测了巨噬细胞的分布、功能和表型特征。在白血病发展过程中，作为骨髓和脾脏白血病相关巨噬细胞（LAMs）的骨髓（BM）和脾脏中巨噬细胞的分布有所不同。LAMs刺激T-ALL细胞的增殖且具有较高的迁移活性。RNA测序分析显示，BM和脾脏LAMs的基因表达谱存在显著差异。RT-PCR分析表明，LAMs同时表达与M1和M2相关的表型基因，但与B16黑色素瘤的肿瘤相关巨噬细胞相比，它们表达的TGF-β1、VEGF-A和CSF-1水平要低得多。此外，与BM LAMs相比，脾脏LAMs更有效地刺激T-ALL细胞的增殖。而且，LAMs可细分为M1样（CD206(-)）和M2样（CD206(+)）组。尽管CD206(+) LAMs表达的大多数与M1和M2相关的基因水平较高，但CD206(+)和CD206(-) LAMs均刺激T-ALL细胞的增殖。这些结果提示了LAMs的功能和表型特征，其受到器官特异性微环境的影响。我们的研究结果拓宽了我们对从实体瘤到白血病的恶性微环境中巨噬细胞的认识。
