Sphingosine-1-Phosphate Recruits Macrophages and Microglia and Induces a Pro-Tumorigenic Phenotype That Favors Glioma Progression

SIMPLE SUMMARY: A better understanding of the interactions between tumor and non-malignant cells is a priority to develop and improve therapeutic approaches for human glioma. Many lines of evidence have recognized sphingolipids as a family of lipids covering a wide range of functions in mammalian cells, in both physiological and pathological settings, including tumor–stroma crosstalk. In this study, we showed that higher amounts of sphingosine-1-phosphate (S1P) triggered an anti-inflammatory milieu both in vitro and in vivo. Inhibition of S1P signaling restored the anti-tumor response in vitro and improved the overall survival of mice that develop glioblastoma in vivo. The exploration of TCGA datasets allowed us to link high SPHK1 levels with a pro-tumorigenic phenotype in glioma patients, which ultimately resulted in a worse survival outcome. These results highlight the role of S1P in mediating tumor–stroma crosstalk, thus clarifying the power of S1P to be considered as a potential therapeutic target. ABSTRACT: Glioblastoma is the most aggressive brain tumor in adults. Treatment failure is predominantly caused by its high invasiveness and its ability to induce a supportive microenvironment. As part of this, a major role for tumor-associated macrophages/microglia (TAMs) in glioblastoma development was recognized. Phospholipids are important players in various fundamental biological processes, including tumor–stroma crosstalk, and the bioactive lipid sphingosine-1-phosphate (S1P) has been linked to glioblastoma cell proliferation, invasion, and survival. Despite the urgent need for better therapeutic approaches, novel strategies targeting sphingolipids in glioblastoma are still poorly explored. Here, we showed that higher amounts of S1P secreted by glioma cells are responsible for an active recruitment of TAMs, mediated by S1P receptor (S1PR) signaling through the modulation of Rac1/RhoA. This resulted in increased infiltration of TAMs in the tumor, which, in turn, triggered their pro-tumorigenic phenotype through the inhibition of NFkB-mediated inflammation. Gene set enrichment analyses showed that such an anti-inflammatory microenvironment correlated with shorter survival of glioblastoma patients. Inhibition of S1P restored a pro-inflammatory phenotype in TAMs and resulted in increased survival of tumor-bearing mice. Taken together, our results establish a crucial role for S1P in fine-tuning the crosstalk between glioma and infiltrating TAMs, thus pointing to the S1P–S1PR axis as an attractive target for glioma treatment.