Modulation of tumor-associated macrophage phenotype by S1P receptors

Weill Medical Coll Of Cornell Univ, New York NY

Investigators

Linked publications & trials

Abstract

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[unreadable] or 2[unreadable] 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[unreadable], or S1P2[unreadable] 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.