A SINGLE‐CELL ATLAS OF DIFFUSE LARGE B CELL LYMPHOMA

Abstract

Diffuse large B-cell lymphoma (DLBCL) is one of the most common yet aggressive types of B-cell lymphoma and remains incurable in 40% of patients. Herein, we profiled the transcriptomes of 94,324 cells from 17 DLBCLs and 3 control samples using single-cell RNA-sequencing technology, creating a comprehensive single-cell map for tumor and infiltrating immune cells for DLBCL. High degrees of inter- and intratumor heterogeneity were revealed, and we identified 73 gene expression programs expressed in malignant B cells. We further characterized 8 nonmalignant B-cell subclusters and 16 T-cell subclusters from the tumor microenvironment. Six myeloid subclusters were also identified, including the LAMP3+ DC subcluster enriched in ABC-DLBCL. More than 2000 likely cell-cell interactions were further predicted in DLBCL, illustrating a complex and highly dynamic DLBCL tumor microenvironment. Unique to B cell lymphomas, a strong costimulatory CD70-CD27 interaction was predicted between malignant cells and T cells. Furthermore, coinhibitory signals mediated by TIM-3 or TIGIT seemed to be the main driving force for T-cell exhaustion. Finally, we discovered that chronic hepatitis B virus infection may have a significant impact on tumor cell survival and immune evasion in DLBCL. Our results provide new insights into B-cell lymphomagenesis and may facilitate the design of targeted immunotherapy strategies. The research was funded by: Swedish Cancer Society, STINT, CIMED, Radiumhemmet, the Swedish Research Council, and the Knut and Alice Wallenberg Foundation, the Guangdong Enterprise Key Laboratory of Human Disease Genomics, the Shenzhen Key Laboratory of Single-Cell Omics Keywords: aggressive B-cell non-Hodgkin lymphoma, genomics, epigenomics, and other -omics, tumor biology and heterogeneity No conflicts of interests pertinent to the abstract.