Overexpression of sphingosine-1-phosphate receptor 1 and phospho-signal transducer and activator of transcription 3 is associated with poor prognosis in rituximab-treated diffuse large B-cell lymphomas

Abstract

Background: Sphingosine-1-phosphate receptor-1 (S1PR1) and signal transducer and activator of transcription-3 (STAT3) play important roles in immune responses with potential oncogenic roles. Methods: We analyzed S1PR1/STAT3 pathway activation using immunohistochemistry in rituximab-treated diffuse large B-cell lymphomas (DLBCL; N = 103). Results: Nuclear expression of pSTAT3 (but not S1PR1) was associated with non-GCB phenotype (p = 0.010). In univariate survival analysis, S1PR1 expression (S1PR1+) was a poor prognostic factor in total DLBCLs (p = 0.018), as well as in nodal (p = 0.041), high-stage (III, IV) (p = 0.002), and high-international prognostic index (IPI; 3-5) (p = 0.014) subgroups, while nuclear expression of pSTAT3 (pSTAT3+) was associated with poor prognosis in the low-stage (I, II) subgroup (p = 0.022). The S1PR1/pSTAT3 risk-categories, containing high-risk (S1PR1+), intermediate-risk (S1PR1-/pSTAT3+), and low-risk (S1PR1-/pSTAT3-), predicted overall survival (p = 0.010). This prognostication tended to be valid in each stage (p = 0.059 in low-stage; p = 0.006 in high-stage) and each IPI subgroups (p = 0.055 [low-IPI]; p = 0.034 [high-IPI]). S1PR1 alone and S1PR1/pSTAT3 risk-category were significant independent prognostic indicators in multivariate analyses incorporating IPI and B symptoms (S1PR1 [p = 0.005; HR = 3.0]; S1PR1/pSTAT3 risk-category [p = 0.019: overall; p = 0.024, HR = 2.7 for S1PR1-/pSTAT3+ vs. S1PR1+; p = 0.021, HR = 3.8 for S1PR1-/pSTAT3-vs. S1PR1+]). Conclusions: Therefore, S1PR1 and S1PR1/pSTAT3 risk-category may contribute to risk stratification in rituximab-treated DLBCLs, and S1PR1 and STAT3 might be therapeutic targets for DLBCL.