CD169阳性巨噬细胞在肿瘤免疫应答中的作用及其调控机制

Macrophages (Mφ) are heterogeneous which are comprised of different subsets. Under the influence of local conditions, Mφ acquire specialized phenotype with diverse functional programs. We recently found that the presence of tumor macrophages was related with a poor prognosis in patients with HCC, whereas high macrophage infiltration was associated with a good prognosis in patients with gastric cancer. Although pan- Mφ infiltration have conflicting prognosis significance in HCC, gastric cancer, high densities of CD169+ Mφ in tumoral tissues are associated with good prognosis of these tumors. Furthermore，CD169+ Mφ in HCC tissue exhibit activation status , the number of CD169+ Mφ is positively corrected with CD8+ T cells in the intra-tumoral area.These results indicated that CD169 might be a candidate marker for a anti-tumoral functionally distinct Mφ subpopulation in human tumors. Based on these observations, we will combine clinical sample analysis and experimental studies to: 1). Examine the phenotype and function of CD169+ Mφ. 2). investigate the effect of CD169 expression on Mφ on the proliferation and functional activities of NK and T cell subsets; dissect the underlying mechanisms for antitumoral function of CD169+ Mφ subsets. 3). Define the key molecules that regulate the expression of CD169 on Mφ, investigate the regulation of phenotype as novel target for cancer prevention and cure. The results obtained from this project will not only reveal the molecular mechanisms about how CD169+ Mφ regulate the development of cancer, but also provide molecular basis for the development of therapeutic strategies that are targeted to modify particular subpopulations of Mφ.

巨噬细胞（Mφ）可根据微环境的变化而展现出不同的功能表型，Mφ具有异质性并存在不同的亚群。我们新近观察到：肝癌组织中Mφ增多与患者术后生存负相关，胃癌组织中Mφ数量却与病人良好预后正相关。但不同于Mφ总数量的预后结果，肿瘤组织中CD169+Mφ的浸润都与良好预后相关。此外，组织原位的CD169+Mφ呈现活化表型，其数量与CD8+T细胞正相关。提示：CD169＋Mφ可能代表了一群新的具有抗肿瘤特性的Mφ亚群。本课题拟结合临床样本分析和实验模型确认CD169＋Mφ的抗肿瘤效应，研究Mφ上CD169表达对NK、T淋巴细胞功能及亚群分化的影响，揭示CD169+Mφ抗肿瘤免疫的机制；阐明调控CD169表达的关键分子，探讨通过调控CD169表达来重建或恢复Mφ抗肿瘤功能的可行性。所得的结果不仅有助于理解Mφ在肿瘤发生发展过程中的作用，也可为以调控Mφ表型/功能或亚群组成为靶标的新型防治策略提供基础。

巨噬细胞（Mφ）可根据微环境的变化而展现出不同的功能表型，Mφ具有异质性并存在不同的亚群，但人体肿瘤中仍缺乏能有效区分Mφ亚群的标记。CD169是唾液酸黏附素（Siglec）家族的成员之一。我们发现：在肝癌肿瘤组中CD169主要表达在Mφ上，并且肿瘤中CD169＋Mφ的数量和CD169表达强度均显著著低于癌旁。CD169+Mφ数量随疾病进展减少并与患者预后呈正相关，提示CD169的表达可能代表了一类具有抗肿瘤作用的Mφ亚群，而肿瘤调控CD169+Mφ的减少很可能是一种肿瘤瘤免疫逃逸的新机制。体外模型中肿瘤上清刺激Mφ自分泌产生的TGF-β可下调其自身CD169的表达。在肝癌组织中，CD169+Mφ呈现出免疫活化表型，能够促进Tc1/Th1反应，而CD169-Mφ却具有免疫抑制表型和功能。阻断CD169可抑制CD169+Mφ诱导的 Tc1／Th1活化：重组人CD169蛋白则会激活Tc1/Th1免疫反应，提示CD169分子可能通过促进 Tc1/Th1免疫反应来实现其抗肿瘤功能。所得的结果不仅有助于理解Mφ在肿瘤发生发展过程中的作用，也可为以调控Mφ表型／功能或亚群组成为靶标的新型防治策略提供基础。