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717 Emergence of Highly-Plastic B Cell States Cooperates with Early Immune Microenvironment Remodeling to Drive Follicular Lymphomagenesis

Program: Oral and Poster Abstracts
Type: Oral
Session: 603. Lymphoid Oncogenesis: Basic: Epigenetic, Immune-Related, and Signaling Mechanisms of Lymphomagenesis
Hematology Disease Topics & Pathways:
Research, Fundamental Science, Translational Research, Lymphomas, non-Hodgkin lymphoma, B Cell lymphoma, genomics, bioinformatics, Diseases, indolent lymphoma, immune mechanism, immunology, Lymphoid Malignancies, computational biology, Biological Processes, molecular biology, Technology and Procedures, Study Population, pathogenesis, Animal model, omics technologies
Monday, December 11, 2023: 11:00 AM

Gabriel Brisou1,2*, Sabrina Baaklini, PhD1*, Noushin Mossadegh-Keller, PhD1*, Alicia Beyou1*, Manon Zala3*, Laurine Gil1*, Camille Soun1*, Caroline Huber1*, Iñaki Cervera-Marzal1*, Agnés Bru1*, Delphine Potier, PhD4*, Stéphanie Gon, PhD4*, Lionel Chasson1*, Asier Antoranz, PhD5*, Jon Pey Perez, PhD5*, Anita K. Gandhi, PhD6, Yumi Nakayama, PhD6*, Patrick R Hagner, PhD7*, Pierre Milpied, PhD1*, Bertrand Nadel, PhD8 and Sandrine Roulland, PhD9*

1Aix Marseille Université, CNRS, INSERM, Centre d'Immunologie de Marseille-Luminy, Marseille, France
2Institut Paoli-Calmettes, Department of Hematology, Marseille Cedex 09, France
3Université Lyon 1, Centre International De Recherche En Infectiologie, Pierre-Benite, France
4Cancer Research Center of Marseille, CNRS, INSERM, Aix Marseille University, Marseille, France
5Intelligent Biodata Ltd, San Sebastian, Spain
6Bristol Myers Squibb, Princeton, NJ
7Translational Development and Diagnostics, Bristol Myers Squibb, Summit, NJ
8Centre D'Immunologie De Marseille-Luminy, Marseilles, France
9Centre d' Immunologie de Marseille - Luminy, Marseille, Cedex 09, France

Follicular lymphoma (FL) is a prototypical example of B cell lymphoma arising from germinal center (GC) B cells. Recent single cell transcriptomic studies investigating the transcriptional heterogeneity of FL suggest that tumor B cells are functionally diverse with cells acquiring an intermediate phenotype between GC and memory (mem), in line with the premalignant FL ontogeny where BCL2+ memory B cells require multiple re-entries into the GC to facilitate the transformation process. Since FL cells often hijack the epigenetic machinery through mutations in histone modifying proteins - notably KMT2D – we questioned here how epigenetic alterations contribute to the emergence of this intratumoral heterogeneity.

We developed a genetically engineered mouse FL-like model (GEMM) carrying Kmt2d loss-of-function in B cells and BCL2 overexpression recapitulating different progression stages from preneoplastic hyperplasia to FL-like tumors. We analyzed 45,541 high-quality single cell transcriptomes and immune repertoires (B cell receptor, BCR and T cell receptor, TCR) from 18 mice including immunized-control mice in the context of physiological GC reaction. We developed a computational workflow on mutant B cells combining supervised and unsupervised metaclustering approaches in order to highlight recurrent gene programs active in preneoplastic hyperplasia and the various stages leading to FL-like tumors. We used inferCNV to assess the association between genetics and transcriptomic heterogeneity and inferred cell-cell interactions to characterize the microenvironmental determinants associated with B cell heterogeneity throughout FL progression.

By modeling the GC cycle dynamics and building B cell signatures during a normal immune response, we found that our FL GEMM mirrored the desynchronization of the GC reaction program previously observed in human FL. Single cell expression profiles of Kmt2d-BCL2 mutant cells also showed a reproducible increase in phenotypic heterogeneity during FL progression, manifesting as a continuum of cell states from proliferating GC-like to quiescent mem-like cell states. We defined this GC-to-Mem axis as the major source of intra-tumor transcriptional heterogeneity. Single-cell BCR sequencing revealed the emergence of highly-plastic B cell states during FL evolution, co-existing within individual mice and being largely independent of subclonal genetic variation. To further elucidate the emergence and maintenance of these cell state transitions, we explored the phenotypic and transcriptional changes within the immune microenvironment along disease progression. Significant compositional changes were found, including the expansion of T follicular helper cells and T regulatory T cells together with the loss of naive CD4, CD8 T, and NK cell populations, preceding malignant transformation and creating a (pre)tumoral supportive niche persisting in advanced tumors. Prior remodeling of a premalignant supportive immune niche may be crucial in establishing malignant cell heterogeneity. Ongoing efforts aim to impair tumor-immune interactions driving tumor B cell dynamics and survival.

In conclusion, our results provide a high-resolution view of events spanning FL progression and indicate a major role of early TME remodeling in establishing a suitable niche for progression. Early intervention aimed to target the B cell-tumor microenvironment interactions driving intra-tumoral heterogeneity may represent a promising therapeutic avenue against early disease and prevention of FL recurrence.

Disclosures: Brisou: Novartis: Consultancy. Gandhi: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Nakayama: BMS: Current Employment. Hagner: BMS: Current Employment, Current equity holder in publicly-traded company. Milpied: BMS: Research Funding. Nadel: BMS: Research Funding; diatech pharmacogenetics: Consultancy, Honoraria. Roulland: BMS: Consultancy, Other: Travel Support, Research Funding.

*signifies non-member of ASH