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Intratumor heterogeneity and T cell exhaustion in primary CNS lymphoma

BACKGROUND: Primary central nervous system lymphoma (PCNSL) is a rare lymphoma of the central nervous system, usually of diffuse large B cell phenotype. Stereotactic biopsy followed by histopathology is the diagnostic standard. However, limited material is available from CNS biopsies, thus impeding...

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Detalles Bibliográficos
Autores principales: Heming, Michael, Haessner, Svea, Wolbert, Jolien, Lu, I-Na, Li, Xiaolin, Brokinkel, Benjamin, Müther, Michael, Holling, Markus, Stummer, Walter, Thomas, Christian, Schulte-Mecklenbeck, Andreas, de Faria, Flavia, Stoeckius, Marlon, Hailfinger, Stephan, Lenz, Georg, Kerl, Kornelius, Wiendl, Heinz, Meyer zu Hörste, Gerd, Grauer, Oliver M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9509601/
https://www.ncbi.nlm.nih.gov/pubmed/36153593
http://dx.doi.org/10.1186/s13073-022-01110-1
Descripción
Sumario:BACKGROUND: Primary central nervous system lymphoma (PCNSL) is a rare lymphoma of the central nervous system, usually of diffuse large B cell phenotype. Stereotactic biopsy followed by histopathology is the diagnostic standard. However, limited material is available from CNS biopsies, thus impeding an in-depth characterization of PCNSL. METHODS: We performed flow cytometry, single-cell RNA sequencing, and B cell receptor sequencing of PCNSL cells released from biopsy material, blood, and cerebrospinal fluid (CSF), and spatial transcriptomics of biopsy samples. RESULTS: PCNSL-released cells were predominantly activated CD19(+)CD20(+)CD38(+)CD27(+) B cells. In single-cell RNA sequencing, PCNSL cells were transcriptionally heterogeneous, forming multiple malignant B cell clusters. Hyperexpanded B cell clones were shared between biopsy- and CSF- but not blood-derived cells. T cells in the tumor microenvironment upregulated immune checkpoint molecules, thereby recognizing immune evasion signals from PCNSL cells. Spatial transcriptomics revealed heterogeneous spatial organization of malignant B cell clusters, mirroring their transcriptional heterogeneity across patients, and pronounced expression of T cell exhaustion markers, co-localizing with a highly malignant B cell cluster. CONCLUSIONS: Malignant B cells in PCNSL show transcriptional and spatial intratumor heterogeneity. T cell exhaustion is frequent in the PCNSL microenvironment, co-localizes with malignant cells, and highlights the potential of personalized treatments. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13073-022-01110-1.