Intratumor heterogeneity and T cell exhaustion in primary CNS lymphoma

• Published in: Genome medicine Vol. 14; no. 1; pp. 109 - 19
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 24-09-2022; BioMed Central; BMC
• Subjects: Antigens; Biopsy; Blood; CD19 antigen; CD20 antigen; CD27 antigen; CD38 antigen; Central nervous system; Central Nervous System Neoplasms - diagnosis; Central Nervous System Neoplasms - genetics; Central Nervous System Neoplasms - pathology; Cerebrospinal fluid; Flow cytometry; Gene expression; Genetic transcription; Genomes; Genomics; Humans; Immune checkpoint; Immune Checkpoint Proteins; Intratumoral heterogeneity; Lymphocytes B; Lymphocytes T; Lymphoma; Lymphoma - diagnosis; Lymphoma - genetics; Lymphoma - pathology; Methods; Nervous system; Non-Hodgkin's lymphomas; Pathogenesis; Patients; Phenotypes; Primary central nervous system lymphoma; Receptors, Antigen, B-Cell; RNA; RNA sequencing; Single-cell RNA sequencing; Spatial transcriptomics; T cell exhaustion; T cells; T-Lymphocytes; Transcription; Transcriptomics; Tumor Microenvironment; Denmark; Germany; T cell exhaustion; Flow cytometry; Primary central nervous system lymphoma; Single-cell RNA sequencing; Spatial transcriptomics; Intratumoral heterogeneity
• ISSN: 1756-994X; 1756-994X
• DOI: 10.1186/s13073-022-01110-1

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.
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.
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.
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.