Plasmablast-like lymphoma cells as a distinct subpopulation confers multidrug resistance in PCNSL

Abstract Background Primary central nervous system lymphoma (PCNSL) is a highly aggressive subtype of non-Hodgkin lymphoma that is confined to the central nervous system. PCNSL is associated with a poor 5-year survival rate of 30-40%, partly due to a high recurrence rate of 60%. A comprehensive understanding of the molecular signatures and mechanisms underlying drug resistance in PCNSL is crucial, as it has significant implications for therapeutic strategies. Methods A cohort of 56 newly diagnosed PCNSL patients was generated. The tumor specimens were obtained by biopsy. A combined approach, including single-cell transcriptomics and B-cell receptor sequencing, transcriptome-informed multiplex immunohistochemistry, and ex-vivo drug response assays, was applied to reveal the transcriptional and immune microenvironment landscape of PCNSL. Results We identify four main B cell subtypes, each characterized by distinct transcriptomic profiles, from malignant B cells in PCNSL. Among these subtypes, plasmablast-like lymphoma cells (PBLCs), characterized by upregulated genes typically associated with plasma cell differentiation, comprise 1.3%-8.1% of malignant B cells and correlate with poor prognosis in PCNSL. PBLCs exhibit reduced expression of CD20, Bruton tyrosine kinase, and FAS, resulting in drug resistance and immune evasion. In addition, PBLCs elevate the expression of critical transcription factors, including XBP1 and PRDM1, to maintain their phenotype. Clinical drugs, such as Lenalidomide, demonstrate potential cytotoxic effects on PBLCs. Conclusions These findings highlight PBLCs as a distinct subtype of malignant B cells that plays a critical role in the multidrug resistance of PCNSL and reveal the molecular signature of PBLCs that can be targeted for therapy.