Modulation of tumor-associated macrophage phenotype by S1P receptors

描述(申请人提供)：肿瘤的发展和生长是由肿瘤支持和促血管生成分子驱动的，这些分子是由被招募到肿瘤微环境的细胞产生的。单核细胞和巨噬细胞(Mono/MF)被认为是作为促炎抗肿瘤细胞(M1)被招募到肿瘤中，然后被驱动到抗炎、促肿瘤表型(M2)，从而招募更多的M2细胞。尽管体外研究表明脂质鞘氨醇-1-磷酸(S1P)可能影响MF的表型，但在体内这种情况如何发生尚不清楚。S1P利用五种受体，其中两种(S1P1和S1P2)是免疫调节剂，传递相反的生物信号：S1P1具有抗炎作用，S1P2具有促炎作用。尽管S1P在肿瘤发生中对MF表型具有重要意义，但目前尚不清楚S1P如何指导表型决定以及S1P1和2如何不同地影响表型决定。项目摘要：利用ID8小鼠卵巢癌细胞株，将在体外和体内阐明S1P1和S1P1在单核/微球集落和表型决定中的作用，以及随后对微球介导的肿瘤生长和血管生成的影响。其具体目的是：(1)在体外阐明S1P1和2信号在表型调控中的作用；(2)确定S1P1和S2在体内对募集和表型的不同贡献。在体外，将通过检测蛋白标记物和功能表型分析中的细胞反应来评估S1P1或2信号如何影响Mono/Mf表型。将使用S1P1和2的特定激动剂和拮抗剂，并用从S1P1？或2？小鼠分离的细胞证实结果。这些受体在MF迁移和支持肿瘤发生中的作用将通过在WT、S1P1或S1P2动物中诱导的ID8卵巢癌模型在体内进一步阐明。公共卫生相关性：破译S1P如何介导肿瘤相关免疫细胞的招募和活性，如TAMS，可能通过将TAMS转换为抗肿瘤细胞类型来为诱导抗肿瘤免疫提供新的治疗途径。这将下调肿瘤支持活动，并上调抗肿瘤免疫反应的其他部分，从而导致更有效的抗肿瘤治疗。

DESCRIPTION (provided by applicant): Tumor development and growth are driven by tumor-supportive and pro-angiogenic molecules produced by cells recruited to the tumor microenvironment. Monocytes and macrophages (mono/MF) are believed to be recruited to the tumor as pro-inflammatory anti-tumor cells (M1) and then driven to an anti-inflammatory, pro-tumor phenotype (M2), which recruit more M2 cells. How this occurs in vivo is unclear, although in vitro studies indicate that the lipid sphingosine-1-phosphate (S1P) may affect MF phenotype. S1P utilizes five receptors, two of which (S1P1 and S1P2) are well-characterized immunomodulators and transduce opposing biological signals: S1P1 is characterized as anti-inflammatory and S1P2 as pro-inflammatory. Despite the implicated importance of S1P to MF phenotype in tumorigenesis, it is unknown how S1P directs phenotype decision and how S1P1 and 2 differentially affect this. Project Summary: The roles of S1P1 and 2 in mono/MF recruitment and phenotype decision, and the subsequent effect on MF-mediated tumor growth and angiogenesis will be clarified in vitro and in vivo using the ID8 mouse ovarian carcinoma cell line. The Specific Aims will: (1) clarify in vitro the contribution of S1P1 and 2 signaling to the modulation of TAM phenotype and (2) determine the differential contribution of S1P1 and 2 to TAM recruitment and phenotype in vivo. In vitro, how S1P1 or 2 signaling affect mono/MF phenotype will be assessed by examining protein markers and cellular responses in functional phenotype assays. Specific agonists and antagonists of S1P1 and 2 will be used and results confirmed with cells isolated from S1P1¿ or 2¿ mice. The roles of these receptors in MF migration and the support of tumorigenesis will be further delineated in vivo using the ID8 ovarian carcinoma model induced in WT, S1P1¿, or S1P2¿ animals. PUBLIC HEALTH RELEVANCE: Deciphering how S1P mediates the recruitment and activity of tumor-associated immune cells, such as TAMs, may offer new avenues of treatment for the induction of anti-tumor immunity by switching TAMs to an anti-tumor cell type. This would both down-regulate tumor-supportive activity and up-regulate other arms of the anti-tumor immune response, leading to more effective anti-tumor therapies.