Sphingosine-1 Phosphate: A New Modulator of Immune Plasticity in the Tumor Microenvironment

Abstract

In the last 15 years, increasing evidences demonstrate a strong link between sphingosine-1-phosphate (S1P) and both normal physiology and progression of different diseases, including cancer and inflammation. Indeed, numerous studies show that tissue levels of this sphingolipid metabolite are augmented in many cancers, affecting survival, proliferation, angiogenesis, and metastatic spread. Recent insights into the possible role of S1P as a therapeutic target has attracted enormous attention and opened new opportunities in this evolving field. In this review, we will focus on the role of S1P in cancer, with particular emphasis in new developments that highlight the many functions of this sphingolipid in the tumor microenvironment. We will discuss how S1P modulates phenotypic plasticity of macrophages and mast cells, tumor-induced immune evasion, differentiation and survival of immune cells in the tumor milieu, interaction between cancer and stromal cells, and hypoxic response.

Keywords: inflammation; macrophage polarization; metastasis; sphingosine-1-phosphate; tumor microenvironment.

Figure 1

S1P metabolism and inside-out signaling. Many agonists stimulate cytosolic sphingosine kinase 1 (SphK1), which translocates to the plasma membrane and uses sphingosine as a substrate to generate Sphingosine-1-phosphate (S1P). S1P may be irreversibly degraded by S1P lyase (SPL) or dephosphorylated by S1P phosphatases (SPPs). After being secreted out by specific transporters, S1P binds and activates S1P receptors (S1PR1–5) in an autocrine or paracrine manner and regulates many cellular functions (inside-out signaling). S1P may also function as an intracellular second messenger through the binding of different intracellular partners. Abbreviations: PI3K, phosphatidylinositol 3-kinase; MAPK, mitogen-activated protein kinases; PLC, phospholipase C.

Figure 2

Role of S1P in the tumor microenvironment. (A) S1P induces monocyte recruitment and macrophage polarization. Apoptotic or tumor cells release S1P that binds S1PR1 and recruits circulating monocytes toward the tumor microenvironment. Once they enter the tissues, monocytes differentiate into macrophages with distinct phenotype according to the surrounding signals. In the tumor microenvironment, S1P exhibits many functions; (i) increase macrophage survival; (ii) function as a “come and get me signaling” of dying cells to attract and enhance macrophage migration through the binding of S1PR1, and (iii) stimulate TAM/M2 macrophage polarization by activating S1PR1/2/4. TAMs are characterized by increased Arginase I (Arg I) activity and secrete the anti-inflammatory cytokines IL-4 and IL-10 that further contribute to induce a permissive microenvironment characterized by tumor evasion and chemotherapy resistance. In addition, S1P released from apoptotic cells activates S1PR1/3 in macrophages to upregulate the expression of cycloxoygenase 2 (Cox-2) and stimulate the secretion of prostaglandin E2 (PGE2) that support migration of endothelial cells and angiogenesis, a hallmark of tumor progression. (B) S1P modulates the interaction between tumor and stromal cells. SphK1 expression is upregulated in melanoma cells, increasing the production of S1P. Melanoma cells stimulate the recruitment of dermal fibroblast toward the tumor microenvironment, and S1P induces the differentiation to myofibroblast/cancer-associated fibroblast (CAF). In turn, CAFs display increased SphK1 expression and release S1P that enhances melanoma migration (through S1PR3) and growth. CAF also express α-smooth muscle actin (α-SMA) and secrete growth factors, extracellular matrix (ECM) components, and metalloproteinases (MMP) that augment cancer progression and promote tumor metastasis.

Figure 3

Relation between S1P and hypoxia in the tumor microenvironment. Angiogenic switch is crucial for tumor progression. HIF1α stability in hypoxic tumor cells is associated to SphK1 expression, which is also regulated by HIF1α. In the tumor microenvironment, hypoxic cells release S1P and cytokines (oncostatin M, eotaxin, and IL-6) to induce M2 macrophage/TAM polarization. In turn, stabilization of HIF1α in TAMs is important to stimulate stem cell differentiation and to release VEGF that supports angiogenesis. Importantly, S1P production in hypoxia increases endothelial cell migration through S1PR2 engagement and enhances the development of new vessels with deficient architecture that impairs the delivery of chemotherapeutic drugs.