1. Intratumor heterogeneity and T cell exhaustion in primary CNS lymphoma
- Author
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Michael Heming, Svea Haessner, Jolien Wolbert, I-Na Lu, Xiaolin Li, Benjamin Brokinkel, Michael Müther, Markus Holling, Walter Stummer, Christian Thomas, Andreas Schulte-Mecklenbeck, Flavia de Faria, Marlon Stoeckius, Stephan Hailfinger, Georg Lenz, Kornelius Kerl, Heinz Wiendl, Gerd Meyer zu Hörste, and Oliver M. Grauer
- Subjects
Primary central nervous system lymphoma ,Single-cell RNA sequencing ,Intratumoral heterogeneity ,T cell exhaustion ,Spatial transcriptomics ,Flow cytometry ,Medicine ,Genetics ,QH426-470 - Abstract
Abstract 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.
- Published
- 2022
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