弥漫大B细胞淋巴瘤细胞自分泌MCP-1调节巨噬细胞极化及机制研究

Diffuse large B-cell lymphoma (DLBCL) incidence rates have increased year by year, a part of them have poor clinical outcomes, but the underlying mechanism involved is still unclear. Macrophage (Mφ) is an important component of tumor microenvironment, M2 macrophage polarization is one of the important factors for tumor progression. The mechanism of M2 macrophage polarization in DLBCL is unclear. Monocyte chemoattractant protein-1 (MCP-1), the most representative of the CC chemokine family members, has been regarded to involve in tumor growth, angiogenesis, epithelial mesenchymal transition, and metastasis etc. in recent years. Our preliminary study results allowed us to speculate that autocrine MCP-1 may promote DLBCL progression through chemotactic recruitment of monocytes, aggregation of tumor associated macrophages (TAMs) and induced polarization to type M2. Therefore, the project intends to analyse the expression of MCP-1 and Mφ subsets distribution characteristics in DLBCL, their relationship with disease progression, and the correlation between them; explore the role of autocrine MCP-1 in the regulation of Mφ polarization and the mechanism by in vivo and in vitro experiments. With MCP-1 as a target, this study will understand deeply the mechanism of Mφ polarization in DLBCL and provide a potential target or new approach for the treatment of DLBCL.

弥漫大B细胞淋巴瘤(DLBCL)发病率逐年增加，一部分患者临床预后差，因疾病进展复发而死亡，但相关机制仍不清楚。巨噬细胞(Mφ)是肿瘤微环境的重要组成部分，Mφ向M2型极化是肿瘤进展的重要因素之一。DLBCL内Mφ向M2型极化的调节机制尚不清楚。单核细胞趋化因子-1(MCP-1)，最具代表性的CC趋化因子家族成员，近些年研究表明在肿瘤生长、血管生成、上皮间充质转化、转移等过程中扮演了重要角色。本课题组前期工作让我们推测肿瘤自分泌MCP-1通过趋化招募单核细胞，聚集肿瘤相关巨噬细胞(TAMs)并诱导向M2型极化，从而促进DLBCL疾病进展。本项目拟分析DLBCL中MCP-1表达和Mφ亚群分布特点，及与疾病进展关系，且两者的相关性；体内、外实验证实肿瘤自分泌MCP-1调节DLBCLMφ极化及机制。以MCP-1为靶点，进一步揭示DLBCLMφ极化机制，为今后治疗DLBCL提供实验依据和新思路。

弥漫大B细胞淋巴瘤(DLBCL)发病率逐年增加，一部分患者临床预后差，因疾病进展复发而死亡，但相关机制仍不清楚。巨噬细胞(Mφ)是肿瘤微环境的重要组成部分，Mφ向M2型极化是肿瘤进展的重要因素之一。DLBCL内Mφ向M2型极化的调节机制尚不清楚。单核细胞趋化因子-1(MCP-1)，最具代表性的CC趋化因子家族成员，近些年研究表明在肿瘤生长、血管生成、上皮间充质转化、转移等过程中扮演了重要角色。我们研究发现较正常B淋巴细胞，DLBCL细胞株Ly-8、SUDHL-6、SUDHL-4、SUDHL-2、Ly-10均存在MCP-1表达上调。体外实验发现MCP-1诱导Mφ表达M2型表面标记CD163和CD206，并促进Mφ分泌M2型细胞因子(IL-10、TGF-β、VEGF和Arg-1)。体内实验发现MCP-1促DLBCL肿瘤增殖和转移，招募CD11b+Ly6G-F4/80+肿瘤相关巨噬细胞(TAMs)聚集，并诱导向CD11b+Ly6G-F4/80+CD206+M2极化。MCP-1促DLBCL微环境中TAMs向M2型极化可能与JAK/STAT通路激活有关。