Modulation of tumor-associated macrophage phenotype by S1P receptors

描述（由申请方提供）：肿瘤发育和生长由募集至肿瘤微环境的细胞产生的肿瘤支持和促血管生成分子驱动。 单核细胞和巨噬细胞（mono/MF）被认为是作为促炎性抗肿瘤细胞（M1）被募集到肿瘤中，然后被驱动为抗炎性促肿瘤表型（M2），其募集更多的M2细胞。 这在体内如何发生尚不清楚，尽管体外研究表明脂质鞘氨醇-1-磷酸（S1 P）可能影响MF表型。 S1 P利用五种受体，其中两种（S1 P1和S1 P2）是充分表征的免疫调节剂，并抑制相反的生物信号：S1 P1被表征为抗炎，S1 P2被表征为促炎。 尽管S1 P对MF表型在肿瘤发生中的重要性，但尚不清楚S1 P如何指导表型决定以及S1 P1和2如何差异化地影响这一点。 项目摘要：S1 P1和2在单/MF招募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将在体外和体内使用ID 8小鼠卵巢癌细胞系进行澄清。 具体目标将：（1）阐明体外S1 P1和2信号传导对TAM表型调节的贡献和（2）确定体内S1 P1和2对TAM募集和表型的差异贡献。 在体外，S1 P1或2信号传导如何影响mono/MF表型将通过检查功能表型测定中的蛋白质标志物和细胞应答来评估。 将使用S1 P1和2的特异性激动剂和拮抗剂，并使用从S1 P1 <$或2 <$小鼠分离的细胞确认结果。 这些受体在MF迁移和支持肿瘤发生中的作用将使用在WT、S1 P1 <$或S1 P2 <$动物中诱导的ID 8卵巢癌模型在体内进一步描述。 公共卫生相关性：破译S1 P如何介导肿瘤相关免疫细胞（如TAM）的募集和活性，可能为通过将TAM转换为抗肿瘤细胞类型来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应答的其他分支，从而导致更有效的抗肿瘤疗法。

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.