Modulation of tumor-associated macrophage phenotype by S1P receptors

描述（由申请人提供）：肿瘤的发展和生长是由肿瘤微环境中募集的细胞产生的肿瘤支持和促血管生成分子驱动的。单核细胞和巨噬细胞（mono/MF）被认为作为促炎抗肿瘤细胞（M1）被招募到肿瘤中，然后被驱动成抗炎、促肿瘤表型（M2），后者招募更多的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表型，但体内如何发生尚不清楚。S1P利用五种受体，其中两种受体（S1P1和S1P2）是典型的免疫调节剂，可转导相反的生物信号：S1P1具有抗炎作用，S1P2具有促炎作用。尽管S1P在肿瘤发生过程中对MF表型具有重要意义，但尚不清楚S1P如何指导表型决定，以及S1P1和2如何差异地影响这一决定。项目摘要：利用ID8小鼠卵巢癌细胞系，在体外和体内研究S1P1和2在单核/MF募集和表型决定中的作用，以及随后对MF介导的肿瘤生长和血管生成的影响。具体目标将：(1)在体外阐明S1P1和2信号对TAM表型调节的贡献；(2)确定S1P1和2在体内对TAM募集和表型的差异贡献。在体外，S1P1或2信号如何影响单/MF表型将通过检查蛋白质标记物和细胞反应在功能表型分析中进行评估。将使用S1P1和2的特异性激动剂和拮抗剂，并使用从S1P1或2小鼠分离的细胞证实结果。这些受体在MF迁移中的作用和对肿瘤发生的支持将通过在WT、S1P1¿或S1P2¿动物中诱导的ID8卵巢癌模型在体内进一步描述。公共卫生相关性：破译S1P如何介导肿瘤相关免疫细胞（如tam）的募集和活性，可能通过将tam转换为抗肿瘤细胞类型，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性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.