Abstract Background Primary central nervous system lymphoma (PCNSL) is a rare lymphoid malignancy. Systemic profiling of the PCNSL tumor microenvironment (TME) was previously conducted through gene expression analysis. We investigated the prognostic impact of TME on survival to establish novel prognostic biomarkers in PCNSL patients. Methods We analyzed expression levels of 770 neuroinflammation‐related (NFR) genes via NanoString nCounter technology in tumor samples from 30 PCNSL patients. Genes related to the “recurrence group (RG)” or “non‐recurrence group (NRG)” were identified and validated using whole transcriptomic analysis of an independent PCNSL cohort (n = 30). Results Forty‐five of 770 NFR genes were highly expressed in the RG (3‐year overall survival (OS, 22.2%), compared with the NRG group (3‐year OS 66.7%). Signatures related to glial cells were enriched in the RG‐associated gene set. Multivariate analysis revealed that high expressions of TUBB4A (p = 0.028, HR: 3.88), S100B (p = 0.046, HR: 3.093), and SLC6A1 (p = 0.034, HR: 3.765) were significantly related to death. Expression levels of these three genes were also significantly associated with poor OS in the validation cohort. Immunohistochemical staining against TUBB4A, S100B, and proteins specific to glial cells (GFAP, OLIG2, and CD68) revealed significantly higher positivity in RG glial cells. Conclusion These data suggest that TME‐related genes play a crucial role in the pathogenesis of PCNSL, complementing the well‐known involvement of the NF‐kB signaling pathway. TME targeting, especially glial cell‐specific proteins, may thus open new and complementary avenues of therapy for all stages of PCNSL.
