Role of sphingosine-1-phosphate receptors in the tumor microenvironment: prospects for cancer immunotherapy.

Abstract

Sphingosine-1-phosphate (S1P) is a sphingolipid protein with anti-apoptotic and pro-survival effects on cancer cells via S1P receptors (S1PRs); however, the role of S1PRs in the tumor microenvironment and immune invasion is still unclear. This study investigated the relationship between S1PR expressions and patient survival and clinical manifestations with respect to the tumor microenvironment and immune infiltration. The expression levels of five S1PRs were obtained from The Cancer Genome Atlas pan-cancer database and the Kaplan-Meier survival analysis was performed. We predicted the relationship between S1PRs expression levels and patient survival using the univariate Cox proportional hazard regression model. Subsequently, we analyzed correlations between S1PRs expression and infiltrating immune cell subtypes using the Kolmogorov-Smirnov test and the infiltration levels of immune and stromal cells in each tumor using the ESTIMATE algorithm and Spearman's test. The five S1PRs exhibited significant heterogeneity in their expression levels. The expression levels correlated with overall patient survival; however, anti-apoptotic or pro-apoptotic features varied depending on the cancer type. The variable effects of S1PRs on tumors may be related to TGF-β levels. Our results suggest that S1PRs exert distinct influences on the tumor stem cell index and chemotherapeutic drug sensitivity. This research provides comprehensive information on the importance of S1PRs in the immune microenvironment, stemness score, sensitivity of human cancer drugs, and cancer prognosis. Interestingly, our findings indicate variations in the expression levels and functions of different S1PR family members. This study highlights S1PRs as potential new targets for antitumor (adjuvant) therapy.