Therapeutic targeting of folate receptor-beta expressing tumor-associated macrophages.

近年来，临床和实验研究表明，炎性巨噬细胞，如肿瘤相关巨噬细胞（tumor-associated macrophages，TAMs）在恶性肿瘤中发挥重要作用。我们发现类风湿性关节炎的滑膜巨噬细胞表达叶酸受体β（FRβ），而正常组织和外周血单核细胞中的组织驻留巨噬细胞不表达或表达低水平的FRβ。我们在人恶性肿瘤和裸鼠移植瘤模型中检测了TAM是否表达FRβ，如果是，选择性清除表达FRβ的TAM是否能抑制裸鼠移植瘤模型中的肿瘤生长，我们的结果显示表达FRβ的TAM具有以下新特征：（a）免疫组化分析显示，表达FRβ的TAM存在于胶质母细胞瘤、肺癌和胰腺癌中;（B）同样，在植入大鼠C6胶质瘤模型的裸鼠中存在表达FRβ的TAM;（由重链和轻链Fv部分和假单胞菌外毒素A组成）导入裸鼠中的C6胶质瘤异种移植物中显著地耗尽TAM并降低肿瘤生长和CD 31阳性血管面积;（4）免疫毒素在体外抑制表达FRβ的巨噬细胞产生NO和VEGF，提示表达FRβ的TAMs可能促进胶质母细胞瘤的生长，提示靶向表达FRβ的巨噬细胞可能是一种有效的抗肿瘤治疗方法。

Recently, clinical and experimental evidence suggested that inflammatory macrophages, such as tumor-associated macrophages (TAMs) play important role in malignant tumors. We have shown that synovial macrophages in rheumatoid arthritis express folate receptor β (FRβ) while tissue resident macrophages in normal tissues and peripheral blood monocytes express no or low levels of FRβ. We tested whether TAMs express FRβ in human malignant tumors and nude mice xenograft model and if so, whether selectively elimination of FRβ-expressing TAMs could suppress tumor growth in nude mice model.Our results showed the following novel features of FRβ-expressing TAMs : (a) immunohistochemical analysis revealed that FRβ-expressing TAMs were present in glioblastoma, lung cancer, and pancreatic cancer; (b) also, FRβ-expressing TAMs were present in nude mice implanted with rat C6 glioma model; (c) injection of the anti-FRβ immunotoxin (consisting of heavy and light chain Fv portions and Pseudomonas exotoxin A) into C6 glioma xenografts in nude mice significantly depleted TAMs and reduced tumor growth and CD31-positive vascular area; (d) immunotoxin inhibited NO and VEGF production by FRβ-expressing macrophages in vitro.Our study indicated that FRβ-expressing TAMs may promote tumor growth in glioblastoma, and suggested that targeting FRβ-expressing macrophages could be an effective anti-cancer therapy method.