Our research focuses on the fundamental biology of B cells, the immune system's antibody-producing cells that offer long-lasting protection against infections. We investigate how B cells mature and differentiate following infection or vaccination, and how these processes can be hijacked to drive diseases such as lymphoma and myeloma. By elucidating the mechanisms that govern B cell fate, we uncover how their dysregulation contributes to cancer. Our studies also explore how solid tumours disrupt B cell differentiation pathways, while also examining the role of B cells, plasma cells, antibodies, and tertiary lymphoid structures in tumour growth and progression.
To address these challenges, we integrate fundamental immunology with translational cancer research. Our lab combines human tissue analysis with genetically engineered mouse models to study immune responses in the context of vaccination, infection, and non-communicable diseases, including both haematological and solid malignancies. We employ cutting-edge techniques such as CRISPR genome editing, advanced imaging, and single-cell and spatial multi-omics to investigate early disease states, tumour-immune interactions, and therapeutic vulnerabilities, with a particular focus on how these processes are altered by ageing.
Ultimately, our goal is to uncover novel biological insights and translate these findings into clinical applications. By understanding how immunity evolves throughout the lifespan, we aim to develop age-adapted interventions that preserve protective immune memory while targeting cancer, thereby improving health and resilience in ageing populations.
Germinal center (GC) B cells are pivotal in establishing a robust humoral immune response and long-term serological immunity while maintaining antibody self-tolerance. GC B cells rely on autophagy for antigen presentation and homeostatic maintenance. However, these functions, primarily associated with the light zone, cannot explain the spatiotemporal autophagy upregulation in the dark zone of GCs. Here, combining imaging, molecular, and genomic approaches, we defined a functional mechanism controlling chromatin accessibility in GC B cells during their dark zone transition. This mechanism links autophagy and nuclear lamin B1 dynamics with their downstream effects, including somatic hypermutation and antibody affinity maturation. Moreover, the autophagy-lamin B1 axis is highly active in the aberrant ectopic GCs in the salivary glands of Sj枚gren's disease, defining its role in autoimmunity.
Our investigation uncovers that nanomolar concentrations of salinomycin, monensin, nigericin, and narasin (a group of potassium/ sodium cation carriers) robustly enhance surface expression of CD20 antigen in B-cell-derived tumor cells, including primary malignant cells of chronic lymphocytic leukemia and diffuse large B-cell lymphoma. Experiments in vitro, ex vivo, and animal model reveal a novel approach of combining salinomycin or monensin with therapeutic anti-CD20 monoclonal antibodies or anti-CD20 chimeric antigen receptor T cells, significantly improving non-Hodgkin lymphoma therapy. The results of RNA sequencing, genetic editing, and chemical inhibition delineate the molecular mechanism of CD20 upregulation, at least partially, to the downregulation of MYC, the transcriptional repressor of the MS4A1 gene encoding CD20. Our findings propose the cation carriers as compounds targeting MYC oncogene, which can be combined with anti-CD20 antibodies or adoptive cellular therapies to treat non-Hodgkin lymphoma and mitigate resistance, which frequently depends on the CD20 antigen loss, offering new solutions to improve patient outcomes.
To increase antibody affinity against pathogens, positively selected GC-B cells initiate cell division in the light zone (LZ) of germinal centers (GCs). Among these, higher-affinity clones migrate to the dark zone (DZ) and vigorously proliferate by utilizing energy provided by oxidative phosphorylation (OXPHOS). However, it remains unknown how positively selected GC-B cells adapt their metabolism for cell division in the glycolysis-dominant, cell cycle arrest-inducing, hypoxic LZ microenvironment. Here, we show that microRNA (miR)-155 mediates metabolic reprogramming during positive selection to protect high-affinity clones. Mechanistically, miR-155 regulates H3K36me2 levels in hypoxic conditions by directly repressing the histone lysine demethylase, Kdm2a, whose expression increases in response to hypoxia. The miR-155-Kdm2a interaction is crucial for enhancing OXPHOS through optimizing the expression of vital nuclear mitochondrial genes under hypoxia, thereby preventing excessive production of reactive oxygen species and subsequent apoptosis. Thus, miR-155-mediated epigenetic regulation promotes mitochondrial fitness in high-affinity GC-B cells, ensuring their expansion and consequently affinity maturation.