膀胱癌组织中CD169阳性巨噬细胞亚群的作用及其机制研究

Tumor-associated macrophages (TAMs) have been shown to have both antitumorigenic and protumorigenic functions, which may be due to different tumor microenvironment allowing macrophages (Mφ) to differentiate into distinct subsets. However, there is lack of surface markers to define different Mφ subsets. We have recently observed that CD169 is primarily expressed on the Mφ in many human solid tumors. In human bladder cancer, the level of tumor-infiltrating CD169+Mφ was positively correlated with the density of CD8+T cells，which is an independent prognostic factor for patients overall survival. We used BCG to treat TAMs in vitro, expression of M1 markers were upregulated and expression of M2 markers were downregulated. Notably, CD169 was significantly upregulated on BCG-treated TAMs in vitro. Taken together, these results indicated that CD169 might be a candidate marker for a functionally distinct Mφ subset in human tumors. To determine the effects and underlying regulatory mechanisms of CD169+Mφ on human bladder cancer, we will combine the clinical sample analysis and experimental studies to study: 1). Examine the prognostic significance of CD169+Mφ in human bladder cancer; 2). Define the key molecules and signaling pathways by which CD169+Mφ induce antitumor immune response, paying particular attention to T cell and NK cell proliferation/activation. 3). Explore the role of CD169 in the BCG induction of Mφ cytotoxicity. The results obtained from this project will not only prove CD169 is a specific marker for a functionally distinct Mφ subset in human bladder cancer, but also provide the molecular basis for understanding the regulatory mechanism of BCG immunotherapy.

巨噬细胞（Mφ）在不同肿瘤中具有“抗肿瘤”或“促肿瘤”功能，可能是受不同肿瘤微环境的影响分化为不同的Mφ亚群所致，但目前尚缺乏区分Mφ亚群的特异性标记。经初步筛查我们观察到：CD169在多种实体瘤中能特异性表达在Mφ上。在膀胱癌中，CD169+Mφ数量与CD8+T细胞数量呈正相关；在卡介苗体外诱导肿瘤相关Mφ活化过程中，CD169的表达明显上调。这些结果提示：CD169可能是一群具有抗肿瘤功能的Mφ亚群标记。以此为基础，本课题拟结合临床样本分析和实验模型，研究：1）在膀胱癌临床样本中检测组织浸润CD169+Mφ的预后意义；2）以T细胞和NK细胞增殖/活化作为主要功能参数，研究CD169+Mφ在抗肿瘤免疫应答中的作用和机制；3）探讨CD169在卡介苗诱导Mφ活化过程中的作用。所得结果不仅能明确CD169作为抗肿瘤Mφ亚群标记的可行性，还可为揭示卡介苗免疫治疗的分子机制奠定基础。

巨噬细胞（Mφ）在不同肿瘤中具有“抗肿瘤”或“促肿瘤”功能，可能是受不同肿瘤微环境的影响分化为不同的Mφ亚群所致，但目前尚缺乏区分Mφ亚群的特异性标记。我们筛选得到三个Mφ亚群/表型潜在标记：“抗肿瘤”表型标记CD169以及“促肿瘤”表型标记CD204和Stabilin-1。我们的研究观察到：在膀胱癌中，CD169、CD204和Stabilin-1均能特异性表达在Mφ上。其中CD169+ Mφ数量与CD8+T细胞数量呈正相关，而且CD169+ Mφ能够促进效应性T细胞的增殖与活化。我们在小鼠模型中验证了国产卡介苗能够通过激活效应性T细胞免疫应答抑制膀胱癌进展。在卡介苗体外诱导肿瘤相关Mφ活化过程中，CD169的表达明显升高；Stabilin-1的表达明显下降。这些结果表明CD169是一种具有抗肿瘤功能的Mφ亚群/表型的标记。令人意外的是，组织原位的CD169、CD204和Stabilin-1均能表达于同一Mφ，单因素生存分析显示三者的表达均与患者预后呈负相关，且癌巢Stabilin-1+ Mφ和间质CD204+ Mφ能够作为独立指标预测患者较差的预后。这些结果提示：膀胱癌肿瘤浸润Mφ可能同时表达不同的分子标记，而这些分子生物学功能的综合作用决定了Mφ对肿瘤进展的最终效应。该项目为研究人体肿瘤相关Mφ亚群/表型提供了新的思路。