A single-cell atlas of large B cell lymphomas reveals distinct malignant archetypes predictive of clinical outcomes
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.
Authors
- Kerstin Wenzl (ORCID: https://orcid.org/0000-0002-3363-1795)
- Sahil Seth (ORCID: https://orcid.org/0000-0003-4579-3959)
- Gabriel Brisou (ORCID: https://orcid.org/0000-0003-0771-683X)
- Sandrine Roulland (ORCID: https://orcid.org/0000-0003-2187-1959)
- Philippe Gaulard (ORCID: https://orcid.org/0000-0002-4243-905X)
- Laura K. Hilton (ORCID: https://orcid.org/0000-0002-6413-6586)
- Pierre Milpied (ORCID: https://orcid.org/0000-0003-1873-5358)
- Xubin Li (ORCID: https://orcid.org/0000-0003-1727-9215)
- Pauline Gravelle (ORCID: https://orcid.org/0000-0002-0462-5652)
- C. Chris Huang (ORCID: https://orcid.org/0000-0002-1116-2756)
- Caroline Huber (ORCID: https://orcid.org/0000-0003-3767-2719)
- Sabrina Baaklini
- Corinne Haïoun (ORCID: https://orcid.org/0000-0003-0095-5379)
- Matthew E. Stokes (ORCID: https://orcid.org/0000-0002-1953-1616)
- Anita K. Gandhi (ORCID: https://orcid.org/0000-0001-5512-1625)
- Romain Fenouil
- Michael R. Green (ORCID: https://orcid.org/0000-0001-6309-9472)
- Lionel Spinelli (ORCID: https://orcid.org/0000-0001-9228-8141)
- Marine Pujol (ORCID: https://orcid.org/0009-0009-0008-6119)
- Laurine Gil
- Noushin Mossadegh‐Keller (ORCID: https://orcid.org/0000-0002-7088-3676)
- María Ortiz Estévez
- Romane Trombetta
- Benjamin Rivière (ORCID: https://orcid.org/0000-0002-0597-5400)
- Ryan D. Morin (ORCID: https://orcid.org/0000-0003-2932-7800)
- Peggy Cuillière-Dartigues
- Kostiantyn Dreval (ORCID: https://orcid.org/0000-0002-6214-2843)
- Laila Dahbi
- Jean‐Marc Navarro
- Bertrand Escalière
- Francisco Llamas Gutierrez
- Camille Barthelemy
- Alexandre Sarrabay
- Rahat Hasan
- Camille Laurent
- François Lemonnier
- Céline Pangault
- Mark Isaac Kaplan
- Fabrice Jardin
- Bertrand Nadel
Institutions
- Centre National de la Recherche Scientifique (FR)
- The University of Texas MD Anderson Cancer Center (US)
- Inserm (FR)
- Bristol-Myers Squibb (Germany) (DE)
- Université Paris-Est Créteil (FR)
- Institut Gustave Roussy (FR)
- Centre de Recherches en Cancérologie de Toulouse (FR)
- Bristol-Myers Squibb (United States) (US)
- Assistance Publique – Hôpitaux de Paris (FR)
- Institut universitaire du cancer de Toulouse Oncopole (FR)
- Hôpital Gui de Chauliac (FR)
- Hôpital Pontchaillou (FR)
- Hôpitaux Universitaires Henri-Mondor (FR)
- Bristol-Myers Squibb (Sweden) (SE)
- Laboratoire National Henri Becquerel (FR)
- Centre d’Immunologie de Marseille-Luminy (FR)
- Lymphoma Study Association (FR)
- Institut Paoli-Calmettes (FR)
- Centre Hospitalier Universitaire de Rennes (FR)
- Université de Rennes (FR)
- Université de Rouen Normandie (FR)
Publication Details
- Journal
- Blood
- Published
- 2026-09-17
- DOI
- https://doi.org/10.1182/blood.2026033056
- Primary Topic
- Single-cell and spatial transcriptomics
- Type
- article
- Field-Weighted Citation Impact
- 0.00