Clinicopathologic implications of sphingosine-1-phosphate pathway in extranodal NK/T-cell lymphoma according to immune subtype

Extranodal NK/T-cell lymphoma (NKTL) is an aggressive lymphoma of mainly the natural killer (NK) cell lineage with Epstein–Barr virus infection. The clinicopathologic role of sphingosine-1-phosphate receptor 5 (S1PR5), a known player in NK cell trafficking, has not yet been investigated in NKTL. Herein, we explored the role of S1PR5 expression in NKTL according to immune subtype. A retrospective analysis of 64 patients with NKTL was performed based on immunohistochemical S1PR5 expression, immune subtypes and clinicopathologic variables. S1PR5 was highly expressed in 70% (45/64) of the NKTL patients. The S1PR5high group had lower levels of serum lactic dehydrogenase (LDH) (p = 0.012) than did the S1PR5low group, with tendencies toward a low/intermediate risk (0–1) of the prognostic index of NK cell lymphoma (PINK) and good ECOG performance status (ECOG PS; 0–1). Based on the 4 immune subtypes, immune evasion (IE)-A (n = 37) was the most common subtype with frequent LDH elevation (p = 0.005) and was subdivided by S1PR5 to produce the immune egress subtype (IES), i.e., immune tolerance (n = 2), IE-A-S1PR5high (n = 27), IE-A-S1PR5low (n = 10), IE-B (n = 12) and immune silenced (n = 13). According to the survival analysis, IES was associated with overall survival (OS) in the full cohort (p = 0.010). In addition, the S1PR5 expression was inversely correlated with the ECOG PS (p = 0.041) and predicted favorable OS in patients with the IE-A subtype (p = 0.014). S1PR5 may have a potential prognostic role in NKTL, especially for the IE-A subtype, which requires further validation.