The activation of the NF-κB p65/PD-L1 signaling pathway in AIDS-related PCNSL is related to TNF-α and IFN-γ but not to MYD88 and CD79B mutations

AIDS-related primary central nervous system lymphoma (AR-PCNSL) differs from immunocompetent PCNSL (IC-PCNSL) due to its immune function and higher mortality rates, emphasizing the urgent need for new treatment targets. This study aimed to investigate the role of the NF-κB p65/PD-L1 signaling pathway in AR-PCNSL. A total of 56 PCNSL tissue samples, including 32 AR-PCNSL cases and 24 IC-PCNSL cases, were analyzed for clinicopathological and imaging features. Histopathological examination was conducted using hematoxylin and eosin (HE) staining, PD-L1 immunohistochemistry and Epstein-Barr encoding region (EBER) in situ hybridization. Differentially expressed molecules (DEMs) were identified via bulk RNA-Seq analysis, while functional pathways were explored through Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. MYD88 L265P and CD79B mutations were detected using sanger sequencing. Additionally, RT-PCR was used to measure the mRNA expression levels of TNF-α and IFN-γ in frozen tissues, while western blotting assessed the protein expression levels of p-NF-κB p65, NF-κB p65, and PD-L1 in cell lines. Compared with IC-PCNSL tissues, AR-PCNSL tissues demonstrated significantly more necrosis (p = 0.001). Imaging analysis showed that AR-PCNSLs had lower ADC (Apparent Diffusion Coefficient, ADC) values (p = 0.000) and more frequent annular enhancement signals (p = 0.007) on DWI (diffusion weighted imaging, DWI). The PD-L1 and EBER positivity rates were higher in AR-PCNSL patients. Co-occurring mutations in MYD88 L265P and CD79B were rare in AR-PCNSL, and were found in only 6.7 % (1/15) of samples, while these mutations appeared in 60.0 % (9/15) of the IC-PCNSL patients (p = 0.005). The RNA levels of TNF-α and IFN-γ were significantly higher in AR-PCNSL patients than in IC-PCNSL patients (p = 0.001). Western blot analysis after TNF-α and IFN-γ treatment revealed increased expression of p-P65 protein and PD-L1. This study provides new evidence indicating that TNF-α and IFN-γ mediated activation of the NF-κB p65/PD-L1 signaling pathway may contribute to the pathogenesis of AR-PCNSL.