肿瘤相关巨噬细胞在促进淋巴肿瘤恶性增殖中的作用及机制

Recently many reports demonstrated that tumor associated macrophages (TAM) promoted carcinogenesis, tumor progression, metastasis and angiogenesis. But the detail mechanisms which promote the proliferation of lymphoma throught the activation of TAM is still unknown. The Bruton's tyrosine kinases (Btk) played an important role in TLR4 signaling, which regulated the production of cytokines and chemokines in macrophages. In our fundamental experiment, we demonstrated that EL4 lymphoma induced TAM exhibited higher level of p-Btk in vitro compared with normal macropahges. Interestingly, Btk inhibitor PCI-32765 inhibited the produciton of PGE2 and IL-10 in TAM through suppression of activation of p-Btk. Moreover, the macropahges which expressed different level of Btk promoted the proliferation of EL4 lymphoma in a distinct manner. Thus, the activation of p-Btk in TAM promoted switch of M1 and M2 macrophages. The phosphorylation level of Btk will be a promising indicator for the evaluation of progonosis and responses after the treatment of lymphoma.

研究表明肿瘤相关巨噬细胞（TAM）与淋巴瘤的发生、生长和浸润等过程密切相关，淋巴瘤组织内高密度TAM多提示预后不良。但影响淋巴瘤组织内巨噬细胞活化方向及TAM形成的关键因素尚不明确。布鲁顿酪氨酸激酶（Btk）介导巨噬细胞内信号通路的活化，并调节其各种细胞因子的产生。目前我们研究发现TAM细胞内磷酸化Btk水平较正常巨噬细胞有明显升高，且与促进淋巴瘤细胞恶性增殖的能力成正相关。另一方面，Btk抑制剂PCI-32765可通过降低TAM内Btk磷酸化水平，减少TAM特征性细胞因子（IL-10和PGE2）的释放及其对于淋巴瘤恶性增殖的推动作用。由此我们推测，巨噬细胞内高水平磷酸化Btk可促进正常巨噬细胞发生TAM转化，并可能会成为肿瘤微环境治疗的新靶标。为此，我们拟进一步验证这一推测，并初步分析TAM细胞中Btk活化水平及某些相关调控因子、淋巴瘤疗效和预后的相关性。

肿瘤微环境内的肿瘤相关性巨噬细胞（TAMs）与肿瘤发生、发展密切相关，高密度TAMs浸润是多种类型肿瘤、包括淋巴瘤预后不良的重要因素。TAMs特异产生的细胞因子和趋化因子等与肿瘤细胞表面相应配体结合，参与调节B细胞淋巴瘤增殖、侵袭与转移过程。课题组利用基础分子生物学结合临床队列的研究方法，证实TAMs细胞中的酪氨酸激酶Btk是调控相关细胞因子与趋化因子产生，并诱发B细胞淋巴瘤内BCR信号传导通路（Chronic active B cell receptor signal）持续活化的关键因素。因此，对于TAMs细胞内相关激酶与信号通路的有效调控和抑制将成为B细胞淋巴瘤免疫治疗的重要方向。.截止至项目结题，课题组共发表相关SCI论文6篇，参加国际及国内会议交流各1次，培养研究生3名。