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.
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.
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| Blaho, Victoria A; Galvani, Sylvain; Engelbrecht, Eric et al. (2015) HDL-bound sphingosine-1-phosphate restrains lymphopoiesis and neuroinflammation. Nature 523:342-6 |
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| Thangada, Shobha; Khanna, Kamal M; Blaho, Victoria A et al. (2010) Cell-surface residence of sphingosine 1-phosphate receptor 1 on lymphocytes determines lymphocyte egress kinetics. J Exp Med 207:1475-83 |
