Sabrina Baaklini, Alexandre Sarrabay, Camille Barthelemy, Laila Dahbi, Laurine Gil, Noushine Mossadegh-Keller, Sahil Seth, Rahat Hasan, Matthew E Stokes, Jean-Marc Navarro, Caroline Huber, Romain Fenouil, Bertrand Escaliere, Romane Trombetta, Marine Pujol, Kostiantyn Dreval, Laura K Hilton, Xubin Li, Michael R Green, Philippe Gaulard, Benjamin Riviere, Peggy Cuillière-Dartigues, Francisco Llamas Gutierrez, Celine Pangault, Fabrice Jardin, François Lemonnier, Gabriel Brisou, Pauline Gravelle, Camille Laurent, Maria Ortiz Estevez, Kerstin Wenzl, Corinne Haioun, Ryan D Morin, Lionel Spinelli, Chris C Huang, Mark Isaac Kaplan, Anita Krithivas Gandhi, Bertrand Nadel, Sandrine Roulland, Pierre Milpied
Large B cell lymphomas (LBCLs) exhibit significant heterogeneity which leads to disparate treatment response, with up to 40% of patients developing refractory disease or relapsing within the first two years. To understand the cellular and molecular basis of this heterogeneity, we performed single-cell RNA-seq, BCR-seq, and TCR-seq on LBCL tumor biopsies, generating an atlas of 63 LBCL cases, mostly classified as diffuse LBCL, not otherwise specified (DLBCL NOS). We identified five conserved transcriptional archetypes of malignant B cells that co-occur within individual tumors, with varying proportions across patients. Notably, high abundance of Archetype 4, characterized by memory B cell features and quiescence markers, correlated with poor event-free survival following standard immunochemotherapy, a finding which was validated in independent cohorts through deconvolution of bulk RNA-seq data. Our study provides a novel framework for patient stratification based on the quantification of malignant cellular states, with implications for precision therapy of LBCLs.